Noninferiority Randomized Clinical Trial Research Articles

Perioperative Antibiotic Prophylaxis Duration in Patients Undergoing Cystectomy With Urinary Diversion

Perioperative antibiotic prophylaxis (PAP) reduces the incidence of surgical site infections (SSIs). Guidelines recommend 24 hours or less of PAP for cystectomy with urinary diversion; however, evidence specifying optimal PAP duration for this surgery is lacking, and prolonged administration of PAP is common practice. To establish noninferiority of 24-hour PAP vs extended-duration PAP in preventing SSIs within 90 days after cystectomy with urinary diversion. This single-center, noninferiority randomized clinical trial was performed from April 18, 2018, to August 18, 2022, in patients aged older than 18 years undergoing elective open cystectomy with urinary diversion. Exclusion criteria were contraindications to administered drugs and inability to follow study procedures. PAP administered for 24 hours (24-hour PAP group) vs PAP until all catheters and stents were removed (extended PAP group). The primary end point was the rate of SSI, and the secondary end points included all-cause mortality, both within 90 days after surgery. Noninferiority of the 24-hour PAP treatment was assessed by comparing the 90% CI (corresponding to a significance level of α = .05) with the predefined noninferiority margin of 10%. A total of 95 patients were randomly assigned to the 24-hour PAP group (median [IQR] age, 69.3 [63.1-76.8] years; 66 males [69.5%]) and 98 to the extended PAP group (median [IQR] age, 69.5 [60.8-75.5] years; 68 males [69.4%]). Patients in the 24-hour PAP group received PAP for a median of 1 day (IQR, 1-1 day), and patients in the extended PAP group received PAP for a median of 8 days (IQR, 7-10 days). No significant differences in SSIs occurring within 90 days were found (24-hour PAP group, 8 patients [8.4%]; extended PAP group, 12 patients [12.2%]; P = .53). The risk difference for 90-day cumulative SSI incidence was -3.8% (90% CI, -11.1% to 3.4%), establishing noninferiority of 24-hour PAP vs extended PAP to prevent SSI. Mortality was not significantly different between groups. The findings of this randomized clinical trial demonstrate noninferiority of 24-hour PAP vs extended-duration PAP in preventing SSIs within 90 days after cystectomy with urinary diversion and may contribute to antibiotic stewardship efforts in urology. ClinicalTrials.gov Identifier: NCT03305627.

Complication, vertical bone gain, volumetric changes after vertical ridge augmentation using customized reinforced PTFE mesh or Ti-mesh. A non-inferiority randomized clinical trial.

The aim of this non-inferiority randomized clinical trial was to compare the surgical and healing complications, vertical bone gain, and volumetric bone changes after vertical ridge augmentation using two different approaches: customized Ti-reinforced d-PTFE mesh versus customized CAD/CAM Ti-mesh. Fifty patients with vertical bone defects were randomly treated with Ti-reinforced d-PTFE mesh (control group) or CAD/CAM Ti-mesh (test group) and a mix of autogenous bone and deproteinized bovine bone matrix. Surgical and healing complication rates (SCR-HCR), vertical bone gain (VBG), regenerated bone volume (RBV), and regeneration rates (RR and ERR) were recorded and analysed [significance level (α) of 0.05]. Of the 50 patients, 48 underwent bone augmentation surgery. SCR were 4% and 12% in PTFE and Ti-mesh, whereas HCR were 12.5% and 8.3%. VBG were 5.79 ± 1.71 mm (range: 3.2-8.8 mm) in the PTFE group and 5.18 ± 1.61 mm (range: 3.1-8.0 mm) in the Ti-mesh group (p = .233), whereas RBV were 1.46 ± 0.48 cc and 1.26 ± 0.55. RR was 99.5% and 87.0%, demonstrating a statistically significant difference (p = .013). Finally, the values related to pseudo-periosteum, bone density, and implant stability were similar in the two study groups. Osseointegration rates were 98.2% and 98.3%. This study confirmed the non-inferiority of customized CAD/CAM titanium meshes with respect to reinforced PTFE meshes in terms of surgical and healing complications. Although PTFE meshes showed higher vertical bone gain and regeneration rates than Ti-meshes, no significant differences were found.

Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates

Millions of people take vitamin K antagonists (VKAs). Some people who need urgent surgical procedures require rapid VKA reversal to prevent excessive intraoperative bleeding. To evaluate the hemostatic noninferiority of an investigational 4-factor prothrombin complex concentrate (4F-PCC) to a control 4F-PCC for rapid VKA reversal before urgent surgery. This phase 3, double-blind, noninferiority randomized clinical trial (LEX-209) was conducted in 24 hospitals in the US, Russia, Georgia, Belarus, Ukraine, and Romania from June 7, 2017, through November 8, 2021; the study was stopped in February 2022. Participants were adult patients taking VKA who had an international normalized ratio (INR) of 2 or higher and needed urgent surgery with a substantial bleeding risk (≥50 mL). Patients were randomized 1:1 to a single infusion of either the investigational 4F-PCC or the control 4F-PCC. Data analysis followed intention-to-treat and per-protocol approaches. Single intravenous infusion was dosed by body weight and baseline INR. A dose of 25, 35, or 50 IU/kg of investigational 4F-PCC or control 4F-PCC was administered for baseline INR of 2 to less than 4, 4 to 6, or over 6, respectively. The primary end point was hemostatic efficacy at surgery end. An independent adjudication board, blinded to the 4F-PCC treatment allocation, assessed hemostatic efficacy using an objective 4-point scale. A total of 208 patients (median [range] age, 67.5 [31-92] years; 118 males [56.7%]) received the investigational (n = 105) or the control (n = 103) 4F-PCC. The median (range) dose was 25 (16-50) IU/kg in the investigational group and 25 (15-50) IU/kg in the control group, with a median (range) infusion time of 12 (8-50) minutes and 13 (7-30) minutes and a median (range) time from infusion to surgery start of 1.42 (0.25-15.25) hours and 1.50 (0.42-18.50) hours, respectively. Baseline median (range) INR was 3.05 (1.97-21.10) in the investigational group and 3.00 (2.00-11.30) in the control group. In the intention-to-treat analysis, the investigational 4F-PCC was noninferior to the control 4F-PCC, resulting in effective hemostasis in 94.3% of patients vs 94.2% of patients (proportion difference, 0.001; 95% CI, -0.080 to 0.082; P < .001), meeting the prespecified noninferiority margin of 0.15. An INR of 1.5 or lower at 30 minutes after infusion occurred in 78.1% of patients in the investigational group vs 71.8% of patients in the control group (proportion difference, 0.063; 95% CI, -0.056 to 0.181). Thrombotic events (2.9% vs 0%, respectively) and mortality (4.8% vs 1.0%, respectively) were no different than expected for 4F-PCC use. One patient in each treatment group discontinued due to adverse events (cardiac disorders unrelated to 4F-PCC). This randomized clinical trial found that the investigational 4F-PCC was hemostatically noninferior to the control 4F-PCC for rapid VKA reversal in patients needing urgent surgery with considerable bleeding risk; the safety profile of these two 4F-PCCs was similar. These results support the investigational 4F-PCC as a therapeutic option for surgical patients requiring rapid VKA reversal. ClinicalTrials.gov Identifier: NCT02740335.

Comparison of low-dose ketamine to methadone for postoperative pain in opioid addicts: a randomized clinical trial.

Postoperative pain can lead to several complications. The effectiveness of different opioids in relieving pain after surgery has been widely studied. However, managing pain in patients with opioid addiction is still challenging. This study aimed to examine the impact of ketamine and methadone on postoperative pain in patients with addiction. This was a non-inferiority randomized clinical trial. All included patients were monitored for morphine use, pain scores, and vital signs every 3 h. The intervention group received 0.5 mg/kg ketamine administered intravenously every 6 h. The control group received 5 mg of methadone intramuscularly every 8 h. The patient received intravenous morphine if their visual analog scale was above 3. All side effects in each group were recorded. Two hundred and twenty patients were included in this study. There were 127 men (57.7%) with an average age of 57.1 ± 19.5 and 93 women (42.3%) with an average age of 57.1 ± 21.0. There were no significant differences in demographic characteristics between the groups. There was no significant difference in the dose or frequency of morphine administration between groups. There was no significant difference between the groups in pain scores and vital signs at different time points. Drug side effects, including delirium and gastrointestinal symptoms, did not differ significantly between the methadone and ketamine groups. Our clinical data support the hypothesis that ketamine is not inferior to methadone in patients with addiction. Future randomize clinical trials are needed to confirm these observations.

Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression

The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT. This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians. Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses. Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment. In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.

Teaching children pedestrian safety in virtual reality via smartphone: a noninferiority randomized clinical trial.

To evaluate whether child pedestrian safety training in a smartphone-based virtual reality (VR) environment is not inferior to training in a large, semi-immersive VR environment with demonstrated effectiveness. Five hundred 7- and 8-year-old children participated; 479 were randomized to one of two conditions: Learning to cross streets in a smartphone-based VR or learning in a semi-immersive kiosk VR. The systems used identical virtual environments and scenarios. At baseline, children's pedestrian skills were assessed in both VR systems and through a vehicle approach estimation task (judging speed/distance of oncoming traffic on monitor). Training in both conditions comprised at least six 30-min sessions in the randomly assigned VR platform and continued for up to 25 visits until adult-level proficiency was obtained. Following training and again 6months later, children completed pedestrian safety assessments identical to baseline. Three outcomes were considered from assessments in each VR platform: Unsafe crossings (collisions plus close calls), time to contact (shortest time between child and oncoming simulated traffic), and missed opportunities (unselected safe opportunities to cross). Participants achieved adult-level street-crossing skill through VR training. Training in a smartphone-based VR system was generally not inferior to training in a large semi-immersive VR system. There were no adverse effects. Seven- and 8-year-old children can learn pedestrian safety through VR-based training, including training in a smartphone-based VR system. Combined with recent meta-analytic results, the present findings support broad implementation and dissemination of child pedestrian safety training through VR, including smartphone-based VR systems.

Cost-effectiveness of posterior versus anterior surgery for cervical radiculopathy: results from a multicentre randomised non-inferiority trial (FACET)

PurposeFor cervical nerve root compression, anterior cervical discectomy with fusion (anterior surgery) or posterior foraminotomy (posterior surgery) are safe and effective options. Posterior surgery might have a more beneficial economic profile compared to anterior surgery. The purpose of this study was to analyse if posterior surgery is cost-effective compared to anterior surgery.MethodsAn economic evaluation was performed as part of a multicentre, noninferiority randomised clinical trial (Foraminotomy ACDF Cost-effectiveness Trial) with a follow-up of 2 years. Primary outcomes were cost-effectiveness based on arm pain (Visual Analogue Scale (VAS; 0–100)) and cost-utility (quality adjusted life years (QALYs)). Missing values were estimated with multiple imputations and bootstrap simulations were used to obtain confidence intervals (CIs).ResultsIn total, 265 patients were randomised and 243 included in the analyses. The pooled mean decrease in VAS arm at 2-year follow-up was 44.2 in the posterior and 40.0 in the anterior group (mean difference, 4.2; 95% CI, − 4.7 to 12.9). Pooled mean QALYs were 1.58 (posterior) and 1.56 (anterior) (mean difference, 0.02; 95% CI, − 0.05 to 0.08). Societal costs were €28,046 for posterior and €30,086 for the anterior group, with lower health care costs for posterior (€12,248) versus anterior (€16,055). Bootstrapped results demonstrated similar effectiveness between groups with in general lower costs associated with posterior surgery.ConclusionIn patients with cervical radiculopathy, arm pain and QALYs were similar between posterior and anterior surgery. Posterior surgery was associated with lower costs and is therefore likely to be cost-effective compared with anterior surgery.

Apical Suspension Repair for Vaginal Vault Prolapse

The optimal surgical repair of vaginal vault prolapse after hysterectomy remains undetermined. To compare the efficacy and safety of 3 surgical approaches for vaginal vault prolapse after hysterectomy. This was a multisite, 3-arm, superiority and noninferiority randomized clinical trial. Outcomes were assessed biannually up to 60 months, until the last participant reached 36 months of follow-up. Settings included 9 clinical sites in the US National Institute of Child Health and Human Development (NICHD) Pelvic Floor Disorders Network. Between February 2016 and April 2019, women with symptomatic vaginal vault prolapse after hysterectomy who desired surgical correction were randomized. Data were analyzed from November 2022 to January 2023. Mesh-augmented (either abdominally [sacrocolpopexy] or through a vaginal incision [transvaginal mesh]) vs transvaginal native tissue repair. The primary outcome was time until composite treatment failure (including retreatment for prolapse, prolapse beyond the hymen, or prolapse symptoms) evaluated with survival models. Secondary outcomes included patient-reported symptom-specific results, objective measures, and adverse events. Of 376 randomized participants (mean [SD] age, 66.1 [8.7] years), 360 (96%) had surgery, and 296 (82%) completed follow-up. Adjusted 36-month failure incidence was 28% (95% CI, 20%-37%) for sacrocolpopexy, 29% (95% CI, 21%-38%) for transvaginal mesh, and 43% (95% CI, 35%-53%) for native tissue repair. Sacrocolpopexy was found to be superior to native tissue repair (adjusted hazard ratio [aHR], 0.57; 99% CI, 0.33-0.98; P = .01). Transvaginal mesh was not statistically superior to native tissue after adjustment for multiple comparisons (aHR, 0.60; 99% CI, 0.34-1.03; P = .02) but was noninferior to sacrocolpopexy (aHR, 1.05; 97% CI, 0-1.65; P = .01). All 3 surgeries resulted in sustained benefits in subjective outcomes. Mesh exposure rates were low (4 of 120 [3%] for sacrocolpopexy and 6 of 115 [5%] for transvaginal mesh) as were the rates of dyspareunia. Among participants undergoing apical repair for vaginal vault prolapse, sacrocolpopexy and transvaginal mesh resulted in similar composite failure rates at study completion; both had lower failure rates than native tissue repair, although only sacrocolpopexy met a statistically significant difference. Low rates of mesh complications and adverse events corroborated the overall safety of each approach. ClinicalTrials.gov Identifier: NCT02676973.

Efficacy of Dequalinium Chloride vs Metronidazole for the Treatment of Bacterial Vaginosis

Bacterial vaginosis (BV) is a common cause of vaginal infection. First-line treatments of BV are metronidazole and clindamycin. Due to the increase in antibiotic resistance, effective nonantibiotic treatments for BV are needed. To examine whether dequalinium chloride, a broad-spectrum antiseptic, is noninferior to oral metronidazole for the treatment of BV. This phase 4, multicenter, triple-blind, double-dummy, parallel, noninferiority randomized clinical trial was conducted from July 29, 2021, to August 25, 2022, with a 1-month follow-up. Participants were premenopausal women 18 years or older with BV from 11 gynecologic practices and 1 hospital in Poland, Slovakia, and the Czech. Patients were randomized to treatment with dequalinium chloride vaginal tablets (10 mg once daily for 6 days) or oral metronidazole (500 mg twice daily for 7 days). Double-dummy medication kits contained vaginal and oral tablets with placebo and active medication. The main outcome was the noninferiority margin (of 15 percentage points) in the absolute difference in clinical cure rates between dequalinium chloride and metronidazole 7 to 11 days after start of treatment (visit 1). Noninferiority was met if the lower 95% CI for the difference in clinical cure rate was less than 15 percentage points at visit 1. A total of 147 women (mean [SD] age, 36.7 [9.0] years) were treated with dequalinium chloride (n = 72) or metronidazole (n = 75). The clinical cure rates at visit 1 were 64 of 69 (92.8%) for dequalinium chloride vs 69 of 74 (93.2%) for metronidazole in the intention-to-treat population, whereas in the per-protocol population, cure rates were 54 of 58 (93.1%) for dequalinium chloride vs 48 of 53 (90.6%) for metronidazole. The treatment differences of -0.5 percentage points (95% CI, -10.8 to 9.8 percentage points; P = .002) in the intention-to-treat population and 2.5 percentage points (95% CI, -9.4 to 14.4 percentage points; P = .001) in the per-protocol population confirmed the noninferiority of dequalinium chloride. The tolerability of dequalinium chloride was rated as very good by 30 of 50 patients (60.0%) but only by 21 of 54 (38.9%) for metronidazole. Three patients in the metronidazole group suspended treatment due to an adverse event. This randomized clinical trial showed that dequalinium chloride was not inferior to metronidazole for the treatment of BV. Dequalinium chloride had a similarly high cure rate but with better tolerability and fewer adverse events. With a similar efficacy to metronidazole and clindamycin, dequalinium chloride warrants consideration as first-line treatment for BV to help reduce antibiotic consumption. EudraCT: 2020-002489-15.

Unraveling variations and enhancing prediction of successful sphincter-preserving resection for low rectal cancer: A post hoc analysis of the multicenter LASRE randomized clinical trial.

Accurate prediction of successful sphincter-preserving resection (SSPR) for low rectal cancer enables peer institutions to scrutinize their own performance and potentially avoid unnecessary permanent colostomy. The aim of this study is to evaluate the variation in SSPR and present the first artificial intelligence (AI) models to predict SSPR in low rectal cancer patients. This was a retrospective post hoc analysis of a multicenter, noninferiority randomized clinical trial (LASRE, NCT XXXXXX) conducted in 22 tertiary hospitals across China. A total of 604 patients who underwent neoadjuvant chemoradiotherapy (CRT) followed by radical resection of low rectal cancer were included as the study cohort, which was then split into a training set (67%) and a testing set (33%). The primary end point of this post hoc analysis was SSPR, which was defined as meeting all the following criteria: (1) sphincter-preserving resection; (2) complete or nearly complete TME, (3) a clear CRM (distance between margin and tumor of 1mm or more), and (4) a clear DRM (distance between margin and tumor of 1mm or more). Seven AI algorithms, namely, support vector machine (SVM), logistic regression (LR), extreme gradient boosting (XGB), light gradient boosting (LGB), decision tree classifier (DTC), random forest (RF) classifier, and multilayer perceptron (MLP), were employed to construct predictive models for SSPR. Evaluation of accuracy in the independent testing set included measures of discrimination, calibration, and clinical applicability. The SSPR rate for the entire cohort was 71.9% (434/604 patients). Significant variation in the rate of SSPR, ranging from 37.7% to 94.4%, was observed among the hospitals. The optimal set of selected features included tumor distance from the anal verge before and after CRT, the occurrence of clinical T downstaging, post-CRT weight and clinical N stage measured by magnetic resonance imaging. The 7 different AI algorithms were developed and applied to the independent testing set. The LR, LGB, MLP and XGB models showed excellent discrimination with AUROC values of 0.825, 0.819, 0.819 and 0.805, respectively. The DTC, RF and SVM models had acceptable discrimination with AUROC values of 0.797, 0.766 and 0.744, respectively. LR and LGB showed the best discrimination, and all 7 AI models had superior overall net benefits within the range of 0.3-0.8 threshold probabilities. Finally, we developed an online calculator based on the LGB model to facilitate clinical use. The rate of SSPR exhibits substantial variation, and the application of AI models has demonstrated the ability to predict SSPR for low rectal cancers with commendable accuracy.

Timing of fractional flow reserve-guided complete revascularization in patients with ST-segment elevation myocardial infarction with multivessel disease: Rationale and design of the OPTION-STEMI trial

Current guidelines recommend complete revascularization (CR) in hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD). With regard to the timing of percutaneous coronary intervention (PCI) for non-infarct-related artery (non-IRA), recent randomized clinical trials have revealed that immediate CR was non-inferior to staged CR. However, the optimal timing of CR remains uncertain. The OPTION-STEMI trial compared immediate CR and in-hospital staged CR guided by fractional flow reserve (FFR) for intermediate stenosis of the non-IRA. The OPTION-STEMI is a multicenter, investigator-initiated, prospective, open-label, non-inferiority randomized clinical trial. The study included patients with at least 1 non-IRA lesion with ≥50% stenosis by visual estimation. Patients fulfilling the inclusion criteria were randomized into 2 groups at a 1:1 ratio: immediate CR (i.e., PCI for the non-IRA performed during primary angioplasty) or in-hospital staged CR. In the in-hospital staged CR group, PCI for non-IRA lesions was performed on another day during the index hospitalization. Non-IRA lesions with 50%-69% stenosis by visual estimation were evaluated by FFR, whereas those with ≥70% stenosis was revascularized without FFR. The primary endpoint was the composite of all-cause death, non-fatal myocardial infarction, and all unplanned revascularization at 1 year after randomization. Enrolment began in December 2019 and was completed in January 2024. The follow-up for the primary endpoint will be completed in January 2025, and primary results will be available in the middle of 2025. The OPTION-STEMI is a multicenter, non-inferiority, randomized trial that evaluated the timing of in-hospital CR with the aid of FFR in patients with STEMI and MVD. URL: https://www. gov. Unique identifier: NCT04626882; and URL: https://cris.nih.go.kr. Unique identifier: KCT0004457.

Safety and efficacy of repetitive stimulation of the left dorsolateral prefrontal cortex using transcranial focused ultrasound in treatment-resistant depressed patients: A non-inferiority randomized controlled trial protocol

BackgroundAbout 30% of patients diagnosed with major depressive disorder fail with the mainstream pharmacological treatment. Patients who do not achieve clinical remission of symptoms, even with two different antidepressants, are classified with treatment-resistant depression (TDR). This condition imposes an additional burden with increased Disability Adjusted Life Years. Therefore, complementary treatments, such as neuromodulation, are necessary. The transcranial focused ultrasound (tFUS) has emerged in the past few years as a reliable method for non-invasive neuromodulation in humans and may help treat TRD. This study aims to propose a research protocol for a non-inferiority randomized clinical trial of TDR with tFUS. MethodsPatients with documented TRD will be screened upon entering the TRD outpatient clinic at UFMG (Brazil). One hundred patients without a clinical history of other psychiatric illness, anatomical abnormalities on magnetic resonance imaging (MRI), or treatment with electroconvulsive therapy will be invited to participate. Patients will be randomized (1:1) into two groups: 1) treatment with a previously established protocol of transcranial magnetic stimulation; and 2) treatment with a similar protocol using the stimulation. Besides regular consultations in the outpatient clinic, both groups will attend 7 protocolled spaced days of brain stimulation targeted at the left dorsolateral prefrontal cortex. They will also be submitted to 4 sessions of image studies (2 MRIs, 2 positron-emission tomography), 3 of neuropsychological assessments (at baseline, 1 week and 2 months after treatment), the Montgomery-Åsberg Depression Rating Scale to analyze the severity of depressive symptoms. DiscussionThis clinical trial intends to verify the safety and clinical efficacy of tFUS stimulation of the dorsolateral prefrontal cortex of patients with TRD, compared with a previously established neuromodulation method.

Comparison of digital and speculum-guided methods of transcervical Foley catheter insertion in primigravida undergoing cervical ripening at term gestation: a noninferiority randomized clinical trial

BackgroundFoley catheter insertion is frequently utilized for cervical ripening during the induction of labour. However, the insertion failure, safety, maternal side effects, complications and satisfaction of digital compared to speculum-guided Foley catheter placement have not been evaluated in a large trial involving primigravida. ObjectivesThe study aimed to compare the insertion failure rate of digital and speculum-based transcervical Foley catheter placement in primigravida. The co-primary outcome was insertion-associated pain. The secondary outcomes were time required for successful insertion, maternal satisfaction, and maternal complications within 24 hours of Foley insertion. MethodsThis randomized, open-label, parallel-arm, non-inferiority clinical trial was performed in a large tertiary care university hospital. Primigravida >18 years of age with term gestation (≥37 weeks) were included in this study. Additional inclusion criteria for enrolment in this study were singleton pregnancy with a cephalic presentation, intact membrane, Bishop score ≤5 and reassuring pre-induction foetal heart rate tracing. All women planned for cervical ripening were assessed for eligibility and were randomized into digital or speculum arms. Foley catheter insertion was performed in a supine lithotomy position. Vaginal and cervical cleaning were performed before insertion. A 22-French Foley balloon catheter was guided digitally or via speculum to position the bulb at the level of the internal os using water-soluble lubricant. Insertion-associated pain was measured using visual numeric rating scale (VNRS) and maternal satisfaction was assessed using a set of questions. Results469 pregnant women were assessed for eligibility, and 446 patients were enrolled and randomized. The median age of the parturients was 24 (19-40) and 24 (18-38) years, respectively. The body mass index, gestational age at randomization, incidence of post-dated pregnancy and pre-randomization Bishop scores were comparable. Insertion failure was observed in 24 (10.8%) and 17 (7.6%) of women in digital and speculum arm, respectively (RR= 1.41; 95% CI, 0.78-2.55; P=0.25). Requirements of more than one attempt (5.4% vs 3.6%) followed by change in hands (3.6% vs 2.7%) were the most common reasons for insertion failure. The median (interquartile range) VNRS was comparable (6.00 (2-9) vs 5.00 (2-10); p=0.15). The time taken for successful insertion was similar (58 (12-241) vs 54 (10-281); p=0.30). 9.4% and 10.8% of women required additional methods of cervical ripening. More women in the speculum group (41.7% vs 33.2%; P=0.06) felt a medium level of discomfort than digital group. ConclusionInsertion failure and insertion-related pain in the digital approach were comparable to the speculum-guided approach for transcervical Foley catheter insertion in primigravida for cervical ripening. Nevertheless, maternal satisfaction was higher in the digital group due to a lesser level of discomfort.

P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy After Deployment of a Drug-Eluting Stent

P2Y12 inhibitor monotherapy after dual antiplatelet therapy (DAPT; a P2Y12 inhibitor plus aspirin) for a brief duration has recently emerged as an attractive alternative for patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent. To investigate whether P2Y12 inhibitor monotherapy after 3 months of DAPT was noninferior to 12 months of DAPT following PCI with a drug-eluting stent. The Short-Term Dual Antiplatelet Therapy After Deployment of Bioabsorbable Polymer Everolimus-Eluting Stent (SHARE) open-label, noninferiority randomized clinical trial was conducted from December 15, 2017, through December 14, 2020. Final 1-year clinical follow-up was completed in January 2022. This study was a multicenter trial that was conducted at 20 hospitals in South Korea. Patients who underwent successful PCI with bioabsorbable polymer everolimus-eluting stents were enrolled. Patients were randomly assigned to receive P2Y12 inhibitor monotherapy after 3 months of DAPT (n = 694) or 12 months of DAPT (n = 693). The primary outcome was a net adverse clinical event, a composite of major bleeding (based on Bleeding Academic Research Consortium type 3 or type 5 bleeding) and major adverse cardiac and cerebrovascular events (cardiac death, myocardial infarction, stent thrombosis, stroke, or ischemia-driven target lesion revascularization) between 3 and 12 months after the index PCI. The major secondary outcomes were major adverse cardiac and cerebrovascular events and major bleeding. The noninferiority margin was 3.0%. Of the total 1452 eligible patients, 65 patients were excluded before the 3-month follow-up, and 1387 patients (mean [SD] age, 63.0 [10.7] years; 1055 men [76.1%]) were assigned to P2Y12 inhibitor monotherapy (n = 694) or DAPT (n = 693). Between 3 and 12 months of follow-up, the primary outcome (using Kaplan-Meier estimates) occurred in 9 patients (1.7%) in the P2Y12 inhibitor monotherapy group and in 16 patients (2.6%) in the DAPT group (absolute difference, -0.93 [1-sided 95% CI, -2.64 to 0.77] percentage points; P < .001 for noninferiority). For the major secondary outcomes (using Kaplan-Meier estimates), major adverse cardiac and cerebrovascular events occurred in 8 patients (1.5%) in the P2Y12 inhibitor monotherapy group and in 12 patients (2.0%) in the DAPT group (absolute difference, -0.49 [95% CI, -2.07 to 1.09] percentage points; P = .54). Major bleeding occurred in 1 patient (0.2%) in the P2Y12 inhibitor monotherapy group and in 5 patients (0.8%) in the DAPT group (absolute difference, -0.60 [95% CI, -1.33 to 0.12] percentage points; P = .10). In patients with coronary artery disease undergoing PCI with the latest generation of drug-eluting stents, P2Y12 inhibitor monotherapy after 3-month DAPT was not inferior to 12-month DAPT for net adverse clinical events. Considering the study population and lower-than-expected event rates, further research is required in other populations. ClinicalTrials.gov Identifier: NCT03447379.

Strategic treatment pause of first-line immune checkpoint inhibitor + VEGFR-tyrosine kinase inhibitor in patients with good or intermediate risk metastatic renal cell carcinoma (mRCC) in response at 1 year of treatment (SPICI-GETUG R05): A non-inferiority randomized clinical trial.

Strategic treatment pause of first-line immune checkpoint inhibitor + VEGFR-tyrosine kinase inhibitor in patients with good or intermediate risk metastatic renal cell carcinoma (mRCC) in response at 1 year of treatment (SPICI-GETUG R05): A non-inferiority randomized clinical trial.

Ketamine Compared With Morphine for Out-of-Hospital Analgesia for Patients With Traumatic Pain

Pain is a common out-of-hospital symptom among patients, and opioids are often prescribed. Research suggests that overprescribing for acute traumatic pain is still prevalent, even when limits restricting opioid prescriptions have been implemented. Ketamine hydrochloride is an alternative to opioids in adults with out-of-hospital traumatic pain. To assess the noninferiority of intravenous ketamine compared with intravenous morphine sulfate to provide pain relief in adults with out-of-hospital traumatic pain. The Intravenous Subdissociative-Dose Ketamine Versus Morphine for Prehospital Analgesia (KETAMORPH) study was a multicenter, single-blind, noninferiority randomized clinical trial comparing ketamine hydrochloride (20 mg, followed by 10 mg every 5 minutes) with morphine sulfate (2 or 3 mg every 5 minutes) in adult patients with out-of-hospital trauma and a verbal pain score equal to or greater than 5. Enrollment occurred from November 23, 2017, to November 26, 2022, in 11 French out-of-hospital emergency medical units. Patients were randomly assigned to ketamine (n = 128) or morphine (n = 123). The primary outcome was the between-group difference in mean change in verbal rating scale pain scores measured from the time before administration of the study drug to 30 minutes later. A noninferiority margin of 1.3 was chosen. A total of 251 patients were randomized (median age, 51 [IQR, 34-69] years; 111 women [44.9%] and 140 men [55.1%] among the 247 with data available) and were included in the intention-to-treat population. The mean pain score change was -3.7 (95% CI, -4.2 to -3.2) in the ketamine group compared with -3.8 (95% CI, -4.2 to -3.4) in the morphine group. The difference in mean pain score change was 0.1 (95% CI, -0.7 to 0.9) points. There were no clinically meaningful differences for vital signs between the 2 groups. The intravenous morphine group had 19 of 113 (16.8% [95% CI, 10.4%-25.0%]) adverse effects reported (most commonly nausea [12 of 113 (10.6%)]) compared with 49 of 120 (40.8% [95% CI, 32.0%-49.6%]) in the ketamine group (most commonly emergence phenomenon [24 of 120 (20.0%)]). No adverse events required intervention. In the KETAMORPH study of patients with out-of-hospital traumatic pain, the use of intravenous ketamine compared with morphine showed noninferiority for pain reduction. In the ongoing opioid crisis, ketamine administered alone is an alternative to opioids in adults with out-of-hospital traumatic pain. ClinicalTrials.gov Identifier: NCT03236805.

The effectiveness and safety of rectal modular dissection for male middle and low rectal cancer after neoadjuvant chemoradiation therapy: the short-term outcome.

Background: The purpose of this study was to assess the efficacy and safety of rectal modular dissection (RMD) in male patients with middle and low rectal cancer. RMD is a technique used to guide the surgical procedure for rectal mobilization, with the ultimate goal of achieving total mesorectal excision. In order to evaluate the effectiveness of RMD, a single-center, non-inferiority randomized clinical trial was carried out. Methods: Eligible patients were randomly assigned into two groups: the RMD group and the traditional rectal mobilization (TRM) group. Demographic characteristics, perioperative data and pathological results of the surgical specimens were collected for analysis. additionally, assessments of urogenital function and defecation function were conducted for all participants. Results: A total of 103 patients (RMD group 53 patients and TRM group 50 patients) were included to analyzed. There were no significant differences in age, body mass index, ASA classification, and tumor characteristics between two groups. The RMD group had significantly lower blood loss (P = 0.00), shorter operative duration (P = 0.00), and shorter hospital stay (P = 0.04) compared to the TRM group. The complete rate of mesorectal excision was higher in the RMD group (98.1%) compared to the TRM group (86.0%, P = 0.02). In terms of functional outcomes, the RMD group had better evaluation scores for urethral function (IPSS score, P = 0.01), erectile function (IIEF-5 score, P = 0.00) and defecation function (LARS score, P = 0.00) at the one-year postoperative follow-up. The 1-year disease-free survival rate was similar between the two groups (P = 0.28). Conclusions: These results suggest that RMD is an effective and safe approach for achieving total mesorectal excision while promoting better functional outcomes for patients. The trial was registered in Chinese Clinical Trial Registry (ChiCTR2100052094).

Efficacy and safety of diphereline 11.25 mg, microrelin 11.25 mg, and microrelin 3.75 mg in premenopausal patients with breast cancer: a non-inferiority randomized clinical trial

BackgroundDiphereline is a Gonadotropin-Releasing Hormone agonist commonly used in patients with breast cancer. This study aimed to compare the efficacy and safety of one-month and three-month Microrelin injections produced by Homa Pharmed Company with three-month Diphereline injections manufactured by IPSEN, France.MethodsThe study was a non-inferiority randomized clinical trial conducted between 2019 and 2023 on premenopausal women candidates for endocrine therapy. The participants were randomly assigned in blocks of six to one of three groups named A (Diphereline 11.25 mg), B (Microrelin 11.25 mg), and C (Microrelin 3.75 mg). The participants’ menopausal symptoms, estradiol, and FSH serum levels were recorded in three-month intervals for one year. The efficacy of each medication and its side effects were compared among the three groups by statistical analysis during the one-year follow-up.ResultsThe study included 133 patients with breast cancer. A decreasing trend in the serum levels of FSH and estradiol and an increasing trend of menopausal symptoms were recorded during the study. No specific side effects leading to drug disruption, hospitalization, or exclusion from the study were observed. Adjusting the effect of study group and time showed no significant changes in estradiol levels between groups B (p = 0.506) and C (p = 0.607) and group A. Also, serum FSH changes between groups B (p = 0.132) and C (p = 0.104) compared to group A were not significant. Moreover, the menopausal symptoms during the one-year follow-up did not significantly increase in group B (p = 0.108) and C (p = 0.113) compared to group A.ConclusionsIt can be concluded that injections of both Microrelin 11.25 mg and 3.75 mg, produced by Homa Pharmed, Iran, are non-inferior in terms of effectiveness and incidence of menopausal symptoms compared to Diphereline, manufactured by IPSEN, France.Trial registrationIRCT.ir, IRCT20201227049847N1; Registered on 09/01/2021.

Digital CBTI hubs as a treatment augmentation strategy in military clinics: study protocol for a pragmatic randomized clinical trial

BackgroundChronic insomnia is the most prevalent sleep disorder among military service members, and it compromises readiness, performance, and physical and mental health. Cognitive behavioral treatment for insomnia (CBTI) is the standard of care for the treatment of insomnia recommended by the VA/DoD Clinical Practice Guideline, the American Academy of Sleep Medicine, and the American College of Physicians. CBTI is highly effective but has limited scalability. It is often unavailable in clinical settings where service members receive sleep care. Digital technologies offer unique opportunities to scale and broaden the geographic reach of CBTI services and support increased patient access and engagement in behavioral sleep care. This study aims to evaluate the impact and acceptability of digital CBTI hubs to augment military treatment facilities’ capabilities in behavioral sleep medicine.MethodsThis is a multi-site, non-inferiority randomized clinical trial designed to compare the effects of in-person (face-to-face or virtual) insomnia care as usual at three military sleep clinics versus CBTI delivered remotely and asynchronously through digital CBTI hubs. Digital CBTI hubs are led by licensed, certified clinicians who use NOCTEM’s® evidence-based clinical decision support platform COAST™ (Clinician Operated Assistive Sleep Technology). Changes in insomnia severity and daytime symptoms of depression and anxiety will be compared at baseline, at 6–8 weeks, and at 3-month follow-up. Patient satisfaction with insomnia care as usual versus digital CBTI hubs will also be examined. We hypothesize that digital CBTI hubs will be non-inferior to insomnia care as usual for improvements in insomnia and daytime symptoms as well as patient satisfaction with insomnia care.DiscussionDigital technology has a high potential to scale CBTI accessibility and delivery options required to meet the insomnia care needs of military service members. Digital CBTI hubs using COAST offer a novel approach to broaden service members’ access to CBTI and to serve as an augmentation strategy for existing sleep services at military treatment facilities. The pragmatic approach leveraging technology in this trial has the potential to rapidly inform clinical practice within the Defense Health Agency as well as other healthcare systems.Trial registrationClinicalTrials.gov NCT05490550. Registered on 14 July 2023.

Therapeutic efficacy of intravenous lidocaine infusion compared with thoracic epidural analgesia in major abdominal surgery: a noninferiority randomised clinical trial

BackgroundOpen major abdominal surgery is one of the most risky surgical procedures for acute postoperative pain. Thoracic epidural analgesia (TEA) has been considered the standard analgesic approach. In different reports, lidocaine i.v. has been shown to have an analgesic efficacy comparable with TEA. We compared the analgesic efficacy of i.v. lidocaine with thoracic epidural analgesia using bupivacaine in patients undergoing major abdominal surgery. MethodsIn this noninferiority clinical trial, 210 patients were randomised to thoracic epidural bupivacaine with morphine or i.v. lidocaine. Dynamic pain at 24 h after surgery was measured using a numerical pain rating scale (NPR), and morphine consumption was also measured. A difference in i.v. the lidocaine-epidural bupivacaine NPR of ≤1 for dynamic pain was considered a noninferiority margin. ResultsThe NPR for dynamic pain in the lidocaine group at 24 h was between 5.7 (1.8) and 5.2 (1.9) in the epidural group, with a difference of 0.53 (95% confidence interval 0.0–1.0). In the first 24 h, the average difference in morphine consumption was 1.8 mg between the i.v. lidocaine and epidural groups (95% confidence interval 1–3 mg). No differences were found in adverse events or complications associated with the procedures. ConclusionsIntravenous lidocaine is noninferior to thoracic epidural analgesia for acute postoperative pain control in major abdomial surgery at 24 h postoperatively. Clinical trials registrationNCT04017013.