Non-inferiority Trial Research Articles

Comparing stem cell mobilization with chemotherapy and cytokine (G-CSF) versus cytokine alone in myeloma patients (MOCCCA): a randomized phase II, open-label, non-inferiority trial.

In fit patients with newly diagnosed myeloma, high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is considered standard of care. For mobilization of CD34+ cells for ASCT, combined cytotoxic chemotherapy and G-CSF is commonly used. However, the importance of cytostatic chemotherapy for reliable mobilization remains unclear. This prospective randomized phase II non-inferiority trial compared G-GSF only (G) compared to standard chemotherapy/G-CSF (CG) for CD34+ mobilization. The primary endpoint was a less than 15% difference in successful stem cell collection ( ≥ 5.0 × 106 CD34+ cells/kg b.w. in a single day collection procedure without additional stimulation with plerixafor) with the G regimen. 136 patients were 1:1 randomized. With an 18% difference in favor of the CG therapy, the non-inferiority margin was not maintained (95% CI 1%, 34%, p = 0.04). The median total CD34+ yield was 9.99 × 106/kg b.w. in CG patients and 7.42 × 106/kg b.w. in patients with G-CSF alone (p < 0.001). Ultimately, 130 (96%) patients proceeded to HDCT with ASCT. There were no differences in adverse events, hematologic engraftment, quality of life, or pain perception between the groups. Our data indicate that G-CSF only is inferior to chemotherapy with G-CSF for peripheral CD34+ stem cell mobilization. Trial registration SNCTP #: SNCTP000002952; Trials.gov #: NCT03442673.

Tenofovir and Hepatitis B Virus Transmission During Pregnancy: A Randomized Clinical Trial.

Standard care for preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) in highly viremic mothers consists of maternal antiviral prophylaxis beginning at gestational week 28 combined with an HBV vaccine series and HBV immune globulin (HBIG) at birth. However, HBIG is unavailable in some resource-limited areas. To determine whether initiating tenofovir disoproxil fumarate (TDF) at gestational week 16 combined with HBV vaccinations for infants is noninferior to the standard care of TDF at gestational week 28 combined with HBV vaccinations and HBIG for infants in preventing MTCT in mothers with HBV and high levels of viremia. An unblinded, 2-group, randomized, noninferiority clinical trial was conducted in 7 tertiary care hospitals in China. A total of 280 pregnant individuals (who all identified as women) with HBV DNA levels greater than 200 000 IU/mL were enrolled between June 4, 2018, and February 8, 2021. The final follow-up occurred on March 1, 2022. Pregnant individuals were randomly assigned to receive either TDF starting at gestational week 16 with HBV vaccinations for the infant or TDF starting at gestational week 28 with HBV vaccinations and HBIG administered to the infant. The primary outcome was the MTCT rate, defined as detectable HBV DNA greater than 20 IU/mL or hepatitis B surface antigen positivity in infants at age 28 weeks. Noninferiority was established if the MTCT rate in the experimental group did not increase by more than an absolute difference of 3% compared with the standard care group, as measured by the upper limit of the 2-sided 90% CI. Among 280 pregnant individuals who enrolled in the trial (mean age, 28 years; mean gestational age at enrollment, 16 weeks), 265 (95%) completed the study. Among all live-born infants, using the last observation carried forward, the MTCT rate was 0.76% (1/131) in the experimental group and 0% (0/142) in the standard care group. In the per-protocol analysis, the MTCT rate was 0% (0/124) in the experimental group and 0% (0/141) in the standard care group. The between-group difference was 0.76% (upper limit of the 2-sided 90% CI, 1.74%) in all live-born infants and 0% (upper limit of the 2-sided 90% CI, 1.43%) in the per-protocol analysis. Both comparisons met the criterion for noninferiority. Rates of congenital defects and malformations were 2.3% (3/131) in the experimental group and 6.3% (9/142) in the standard care group (difference, 4% [2-sided 95% CI, -8.8% to 0.7%]). Among pregnant women with HBV and high levels of viremia, TDF beginning at gestational week 16 combined with HBV vaccination for infants was noninferior to the standard care of TDF beginning at gestational week 28 combined with HBIG and HBV vaccination for infants. These results support beginning TDF at gestational week 16 combined with infant HBV vaccine to prevent MTCT of HBV in geographic areas where HBIG is not available. ClinicalTrials.gov Identifier: NCT03476083.

Transversus abdominis plane block in minimally invasive colon surgery: a multicenter three-arm randomized controlled superiority and non-inferiority clinical trial

Background and objectivesThe transversus abdominis plane (TAP) block is the most widely used abdominal field block in colorectal surgery with a postoperative enhanced recovery pathway. We aimed to determine whether the laparoscopic-assisted and ultrasound-guided TAP (US-TAP) blocks provide superior pain relief compared with placebo. We separately investigated whether the laparoscopic-assisted technique was non-inferior to the ultrasound-guided technique in providing pain relief, with a non-inferiority margin of 10 mg morphine dose equivalents.Methods340 patients undergoing elective minimally invasive colon surgery were randomly allocated to one of three groups: (1) US-TAP block, (2) laparoscopic-assisted TAP (L-TAP) block, or (3) placebo. Superiority and non-inferiority were tested for the primary outcome: 24-hour postoperative morphine equivalent consumption. Secondary outcomes, including patient-reported quality of recovery, were included in the superiority analysis.Results127 patients were included in each block group and 86 in the placebo group. The US-TAP block was no different from placebo at −1.4 mg morphine (97.5% CI −6.8 to 4.0 mg; p=0.55). The L-TAP block was superior to placebo at −5.9 mg morphine (97.5% CI −11.3 to −0.5 mg; p=0.01) and non-inferior to the US-TAP block at −4.5 mg morphine (98.75% CI −10.0 to 1.1 mg).ConclusionThe L-TAP block was superior to placebo and non-inferior to the US-TAP block. However, neither met our predetermined estimate of the minimal clinically important difference of 10 mg morphine.Trial registration numberNCT04311099.

Orally Administered Peppermint Oil Solution in Small Bowel Capsule Endoscopy: A Novel Approach to Improve Completion Rates in Patients at Risk of Dela

Background and Study Aims Small bowel capsule endoscopy (SBCE) is crucial in diagnosing small bowel diseases, yet incomplete examinations often result from prolonged gastric transit time. This study aimed to assess the efficacy of orally administered peppermint oil solution as a prokinetic agent to improve SBCE completion rates in patients with delayed gastric transit risk factors. Patients and Methods Conducted as a single-centre, prospective, open-label, non-inferiority trial, the study involved 132 patients identified as at risk for delayed gastric transit. Participants were divided into three groups: a peppermint oil solution group (n=57), a real-time monitoring and intravenous prokinetics group (n=75), and a control group without risk factors (n=193). The primary outcomes included SBCE completion rates, gastric transit time (GTT), small bowel transit time (SBTT), diagnostic yield, and bowel preparation quality. Results Completion rates were high and comparable among groups, with 94.7% in the peppermint group, 90.7% in the real-time monitoring group, and 95.3% in the control group. The peppermint group exhibited a significantly shorter mean GTT of 42.3 minutes compared to 57.0 minutes in the real-time monitoring group (p=0.0423). However, the SBTT was longer in the peppermint group at 246 minutes versus 193 minutes in the real-time monitoring group (p=0.0081), though similar to the control group at 228.3 minutes (p=0.2612). Diagnostic yield and bowel preparation quality were consistent across all groups. Conclusion Oral peppermint oil solution is a safe and effective alternative to traditional prokinetics, enhancing SBCE completion rates while reducing time and resource use in the endoscopy unit.

Abstract 4134668: Title: Mandibular advancement device versus CPAP on cardiovascular health and quality of life in OSA a pre-specified 12 months follow up of outcomes

Background: Obstructive sleep apnoea (OSA) is a significant cause of hypertension. ACC/AHA Guidelines recommended screening and treatment of OSA in patients with hypertension; however, evidence comparing mandibular advancement devices (MAD) to continuous positive airway pressure (CPAP) on cardiovascular health is lacking. We present the complete 12 months follow-up data on the comparative effectiveness of MAD versus CPAP in ambulatory BP reduction, QoL, cardiac arrhythmia, and myocardial remodelling. Method: In a randomized, non-inferiority trial (margin 1.5 mmHg), 321 participants, aged over 40, with hypertension and high cardiovascular risk were recruited. Of these, 220 participants with OSA (apnoea–hypopnea index ≥15 events/h) were randomized to either MAD or CPAP (1:1). Pre-specified secondary outcomes include: ambulatory BP, quality of life (QoL) (sleep-specific: ESS, SAQLI, FOSQ; non-sleep-specific: SF-36, EQ-5D), ambulatory ECG monitoring, and cardiac MRI. Results: A total of 89 (80.9% of 110) participants from MAD, and 91 (82.7% of 110) participants from CPAP completed 12 months follow-up. The median daily usage was 5.5 hours for MAD and 4.9 hours for CPAP. The between-group difference in 24h mean BP from baseline to 12 months was - 0.57 mmHg (95% confidence interval: (-2.53 to 1.39, non-inferiority P &lt; 0.001). Compared with the CPAP group, MAD group demonstrated a larger reduction in all the 24h with the most pronounced differences observed in the asleep BP parameters (Table 1). Both the MAD and CPAP improved QoL (Table 2). CPAP had greater improvement in FOSQ from sleep-specific questionnaires (P=0.038), and social QoL in SF-36 from non-sleep-specificl questionnaires (P=0.013). The ambulatory ECG monitoring (MAD: 2.8 ± 1.0 days, CPAP: 2.3 ± 1.1 days) showed no between-group differences in % atrial fibrillation(P=0.209), % ventricular ectopic isolated count (P=0.790) and % supraventricular ectopic isolated count (P= 0.333). The cardiac MRI sub-study (101 participants : MAD= 45, CPAP= 56) showed CPAP had greater improvement in right ventricular stroke volume (P=0.023) and MAD had greater improvement in circumferential strain favours the MAD group (P=0.015) (Table 3). Conclusion: At 12 months , MAD was non-inferior to CPAP for reducing 24h mean arterial BP. MAD showed greater reduction in 24h BPs, especially during asleep. While both the MAD and CPAP are effective in improving QoL, CPAP is more effective in improving FOSQ and social QoL (SF-36).

Modification and Validation of the System Causability Scale Using AI-Based Therapeutic Recommendations for Urological Cancer Patients: A Basis for the Development of a Prospective Comparative Study

The integration of artificial intelligence, particularly Large Language Models (LLMs), has the potential to significantly enhance therapeutic decision-making in clinical oncology. Initial studies across various disciplines have demonstrated that LLM-based treatment recommendations can rival those of multidisciplinary tumor boards (MTBs); however, such data are currently lacking for urological cancers. This preparatory study establishes a robust methodological foundation for the forthcoming CONCORDIA trial, including the validation of the System Causability Scale (SCS) and its modified version (mSCS), as well as the selection of LLMs for urological cancer treatment recommendations based on recommendations from ChatGPT-4 and an MTB for 40 urological cancer scenarios. Both scales demonstrated strong validity, reliability (all aggregated Cohen’s K &gt; 0.74), and internal consistency (all Cronbach’s Alpha &gt; 0.9), with the mSCS showing superior reliability, internal consistency, and clinical applicability (p &lt; 0.01). Two Delphi processes were used to define the LLMs to be tested in the CONCORDIA study (ChatGPT-4 and Claude 3.5 Sonnet) and to establish the acceptable non-inferiority margin for LLM recommendations compared to MTB recommendations. The forthcoming ethics-approved and registered CONCORDIA non-inferiority trial will require 110 urological cancer scenarios, with an mSCS difference threshold of 0.15, a Bonferroni corrected alpha of 0.025, and a beta of 0.1. Blinded mSCS assessments of MTB recommendations will then be compared to those of the LLMs. In summary, this work establishes the necessary prerequisites prior to initiating the CONCORDIA study and validates a modified score with high applicability and reliability for this and future trials.

CTNI-16. MONOGERM, A NOVEL PROOF-OF-PRINCIPLE BAYESIAN PHASE II TRIAL DESIGN OF CARBOPLATIN OR VINBLASTINE MONOTHERAPY INDUCTION PRIOR TO RADIOTHERAPY FOR INTRACRANIAL GERMINOMA

Abstract BACKGROUND Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely. METHODS Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440). RESULTS MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (&amp;lt;30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design. CONCLUSION MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial.

Comparing two transitioning strategies to paliperidone palmitate once-every-6-months.

A double-blind, randomized, active-controlled, parallel-group, noninferiority trial (NCT03345342) demonstrated that paliperidone palmitate once-every-6-months (PP6M) was noninferior to paliperidone palmitate once-every-3-months (PP3M) in preventing relapse in clinically stable adults with schizophrenia. This post hoc analysis assessed efficacy and safety following transition to PP6M from paliperidone once-monthly (PP1M) versus PP3M. Adults with schizophrenia who were clinically stable on moderate/high doses of PP1M or PP3M were randomly assigned 1:2 to dorsogluteal PP3M or PP6M treatment for 12months. The primary efficacy measure was time to relapse during the 12-month DB phase. Secondary endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale (PANSS) total and subscale scores, Clinical Global Impression-Severity (CGI-S) scale score, and Personal and Social Performance (PSP) scale score. Safety was assessed by treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory tests. Of 702 patients in the study, 231 transitioned from PP1M to PP6M and 247 transitioned from PP3M to PP6M. Low relapse rates for PP6M were observed regardless of transition pathway (PP1M/PP6M: 7.8%; PP3M/PP6M: 7.3%). Changes from DB baseline to endpoint in PANSS total, PSP, and CGI-S scores were similar between transition groups. In the DB phase, ≥1 TEAE was observed in 61.0% and 63.2% of patients in the PP1M/PP6M and PP3M/PP6M, groups, respectively. Adults with schizophrenia who transitioned to PP6M from either PP1M or PP3M experienced similarly low relapse rates. Additionally, symptom and functionality scores supported the primary analysis and, along with TEAE incidences, were comparable between transition groups.

Noninferiority Randomized Clinical Trial: KIM Sling With Reusable Trocars Versus TVT Exact Sling.

The Neomedic Knotless Incontinence Mesh (KIM) sling with sterilizable trocars decreases medical waste versus midurethral slings with disposable trocars. Limited comparative data exist. The aim of the study was to assess to the success of the retropubic KIM sling compared to the Gynecare TVT Exact sling. This was a single-center, randomized noninferiority trial comparing outcomes of 2 retropubic slings-KIM sling and TVT Exact sling-in women with stress urinary incontinence from August 2021 to May 2023. Primary outcome was subjective success at 6 weeks defined by a composite outcome of the response to the question #17 on the The Pelvic Floor Distress Inventory-20 questionnaire and no retreatment of stress urinary incontinence. Secondary outcomes included rates of urinary retention, mesh erosion, and reoperation for mesh complications. Sample size estimate based on noninferiority margin of 14%, equal success of 90%, alpha 0.05, and 80% power with a 20% dropout was 72 per group. Among 147 patients, 74 (50.3%) were randomized to KIM sling versus 73 (49.7%) to TVT exact. The rates of 6-week success were 68.5% for the KIM sling and 83.3% for the TVT exact with a risk difference 14.8% (95% confidence interval, 1.1-28.5). The KIM sling is not noninferior to the TVT Exact sling. There were no differences in secondary outcomes. The KIM sling is not noninferior to the TVT Exact sling for success at 6 weeks based on a composite outcome score. This clinical trial is ongoing to assess outcomes at 6 months and 1 year. (Clinicaltrials.gov NCT04985799).

Neoadjuvant and adjuvant toripalimab for locoregionally advanced nasopharyngeal carcinoma: a randomised, single-centre, double-blind, placebo-controlled, phase 2 trial

Patients with locoregionally advanced nasopharyngeal carcinoma with a high pretreatment plasma concentration of Epstein-Barr virus (EBV) DNA remain at high risk for recurrence after concurrent chemoradiotherapy. This study aimed to compare the efficacy and safety of neoadjuvant-adjuvant treatment with the PD-1 inhibitor toripalimab and concurrent chemoradiotherapy versus placebo and concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. This randomised, single-centre, double-blind, placebo-controlled, phase 2 trial was conducted at Sun Yat-sen University Cancer Centre in Guangzhou, China. Adult patients (aged 18-65 years) with newly diagnosed high-risk stage III-IVa locoregionally advanced nasopharyngeal carcinoma, with a pretreatment plasma EBV DNA concentration of at least 1500 copies per mL and an Eastern Cooperative Oncology Group performance score of 0-1, were eligible. Patients were randomly assigned (2:1) using an interactive web response system (block size of six), stratified by TNM stage (III vs IVa), to neoadjuvant toripalimab (240 mg intravenously) or placebo once every 2 weeks for two cycles, followed by concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 during intensity-modulated radiotherapy and adjuvant toripalimab (240 mg intravenously) or placebo once every 3 weeks for up to eight cycles. The primary endpoint was 2-year progression-free survival in the intention-to-treat population. This study was registered with ClinicalTrials.gov, NCT03925090, and is closed to enrolment; follow-up is ongoing. Between Dec 6, 2019, and Dec 9, 2021, 150 patients were enrolled and randomly assigned to the toripalimab group (n=100) or placebo group (n=50). 115 (77%) patients were male and 35 (23%) were female. As of data cutoff (May 31, 2024), median follow-up for progression-free survival was 37·8 months (IQR 34·2-46·5) for the intention-to-treat population analyses. 2-year progression-free survival was higher in the toripalimab group (92·0% [95% CI 86·7-97·3]) than in the placebo group (74·0% [61·8-86·2]; stratified hazard ratio 0·40 [95% CI 0·18-0·89]; log-rank p=0·019). The most common grade 3 or worse acute adverse events (occurring within 1 year of randomisation) were leukopenia (40 [40%] of 99 patients in the toripalimab group vs 22 [44%] of 50 patients in the placebo group), mucositis (28 [28%] vs ten [20%]), neutropenia (17 [17%] vs nine [18%]), anaemia (16 [16%] vs five [10%]), and weight loss (12 [12%] vs six [12%]). The most common grade 3 or worse late adverse events (occurring >1 year after randomisation) was auditory or hearing loss (eight [8%] vs four [8%]). Immune-mediated adverse events of grade 3 or worse occurred in ten (10%) patients only in the toripalimab group. One (2%) of 50 patients in the placebo group died due to septic shock caused by bacteraemia considered not treatment related. There were no treatment-related deaths in the toripalimab group. Our findings suggested that a so-called sandwich approach involving toripalimab (in the neoadjuvant and adjuvant phases) combined with concurrent chemoradiotherapy could be a highly promising therapy for the treatment of locoregionally advanced nasopharyngeal carcinoma. Phase 3 non-inferiority trials are warranted comparing neoadjuvant and adjuvant toripalimab versus cisplatin plus gemcitabine neoadjuvant chemotherapy combined with concurrent chemoradiotherapy. National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Science and Technology Program of Guangzhou, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Postdoctoral Innovative Talent Support Program, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, and Fundamental Research Funds for the Central Universities. For the Chinese translation of the abstract see Supplementary Materials section.

Vadadustat Three Times Weekly in Patients With Anemia Due to Dialysis-Dependent CKD

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) may offer an alternative erythropoiesis-stimulating agents (ESA) for the treatment of anemia in the setting of CKD. To investigate the efficacy and safety of conversion from long-acting erythropoiesis-stimulating agent (ESA) methoxy polyethylene glycol-epoetin beta (MPG-EPO) to the oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) vadadustat 3-times-weekly versus maintenance on MPG-EPO. Phase 3b, open-label, noninferiority trial. Multicenter study in United States; 456 patients adults with anemia and dialysis-dependent chronic kidney disease. Participants were randomized 1:1:1 either to vadadustat (starting dose: 600 mg thrice weekly), vadadustat (starting dose: 900 mg thrice weekly), or MPG-EPO, for up to 52 treatment weeks and 4 safety follow-up weeks after the end of treatment or early termination. Primary and secondary efficacy endpoints were the mean change in hemoglobin from baseline during primary (weeks 20-26) and secondary (weeks 46-52) evaluation periods, respectively. Noninferiority was specified as a lower bound of the 95% CI above -0.75 g/dL for the difference in mean change in hemoglobin from baseline. Other efficacy endpoints were the proportion of participants with hemoglobin levels within the target range and the proportions of participants requiring ESA or red blood cell transfusion rescue for anemia during the evaluation periods. Transfusion rates were low and occurred at similar rates across treatment groups (2.7% and 4.0% in the combined vadadustat and MPG-EPO groups, respectively). Primary safety endpoints were any treatment-emergent and serious adverse events (AEs). After combining the vadadustat groups (600 mg and 900 mg thrice weekly, n=304), vadadustat was noninferior to MPG-EPO (n=152) for both primary (least squares mean treatment difference, -0.33; 95% CI, -0.53 to -0.13) and secondary efficacy endpoints (-0.33; -0.56 to -0.09). Mean hemoglobin concentrations were stable for all groups, except for an initial slight decline in the vadadustat 600 mg group, which stabilized by week 12. ESA rescue for anemia was more frequent in the MPG-EPO group (primary evaluation period, 27.7%; secondary evaluation period, 16.2%) than in the combined vadadustat (14.2%; 7.3%) groups. The incidences of any treatment-emergent and serious treatment-emergent AEs were similar across treatment groups. Potential errors in attribution of AEs as drug related. Three-times-weekly vadadustat was noninferior to MPG-EPO on their effect on hemoglobin levels without detectable differences in AEs.

Comparative study on pregnancy complications: PGT-A vs. IVF-ET with gender-specific outcomes

The safety and clinical effectiveness of preimplantation genetic testing for aneuploidy (PGT-A) in improving pregnancy outcomes for sub-fertile patients remains controversial. Potential sex-based differences in the relationship between PGT-A and pregnancy complications have not been investigated, which could guide the appropriate clinical application of PGT-A. In this secondary analysis of data from a multicenter, randomized, controlled, non-inferiority trial (NCT03118141), 940 women who achieved singleton live birth during the trial were included to estimate the between-group differences in pregnancy complications following PGT-A versus conventional in vitro fertilization (IVF) vary with fetal sex. Logistic regression analysis was used to adjust for possible confounders, and subgroup analysis was also performed. Among male fetuses, the risk of maternal preeclampsia was significantly lower after PGT-A compared to conventional IVF treatment (3.37% vs. 7.88%; adjusted OR, 0.40; 95% CI, 0.17-0.92; P = 0.032). However, this protective effect was not observed in pregnancies with female fetuses (3.63% vs. 3.38%; adjusted OR, 1.04; 95% CI, 0.36-3.00; P = 0.937). In addition, no significant sex-dependent differences in the risks of other pregnancy complications or neonatal outcomes were detected between PGT-A and conventional IVF groups (P &amp;gt; 0.05). In summary, PGT-A was associated with a decreased risk of maternal preeclampsia in singleton pregnancies with male fetuses, highlighting its potential utility in preeclampsia prevention in addition to spontaneous abortion rate reduction.

A randomised trial of sirolimus- versus paclitaxel-coated balloons for de novo coronary lesions.

Paclitaxel-coated balloons (PCB) are a viable alternative to drug-eluting stents in the treatment of de novo coronary lesions. Whether sirolimus represents an alternative to paclitaxel for drug-coated balloons remains elusive. This randomised, controlled, multicentre, non-inferiority trial investigated a novel sirolimus-coated balloon (SCB) with a crystalline coating versus a PCB in de novo coronary lesions. To compare a novel SCB with a clinically proven PCB, 70 patients with de novo coronary lesions were enrolled at 4 centres in Germany and Switzerland. The primary endpoint was non-inferiority regarding angiographic late lumen loss (LLL) at 6 months, with a predefined margin of δ=0.35 mm. Secondary endpoints included procedural success, major adverse cardiac events, and individual clinical endpoints. Quantitative coronary angiography revealed no differences in baseline parameters. At 6 months, in-segment LLL was 0.04±0.39 mm in the PCB group versus 0.11±0.37 mm in the SCB group (non-significant), respectively. The mean difference between SCB and PCB was 0.07 mm (95% confidence interval: -0.12 to 0.26). Non-inferiority at the predefined margin of 0.35 was shown. Clinical event rates up to 12 months were not different between the groups (3 target lesion revascularisations in the PCB group versus 2 in the SCB group, no myocardial infarctions, no deaths). The novel SCB showed similar angiographic outcomes in the treatment of de novo coronary disease as compared with a clinically proven PCB (ClinicalTrials.gov: NCT03908450).

Laparoscopy-assisted versus open surgery for low rectal cancer (LASRE): 3-year survival outcomes of a multicentre, randomised, controlled, non-inferiority trial

Laparoscopic surgery is increasingly used for rectal cancer, but the long-term oncological outcomes for low rectal cancer have not been fully established. We aimed to evaluate the 3-year survival outcomes of laparoscopic surgery versus open surgery in the treatment of low rectal cancer. This multicentre, randomised, controlled, non-inferiority trial was conducted at 22 tertiary hospitals in China. Individuals aged 18-75 years with histologically confirmed cT1-2N0, cT3-4aN0, or cT1-4aN1-2 rectal adenocarcinoma within 5 cm from the dentate line were eligible for inclusion. Participants were randomly assigned (2:1) to undergo laparoscopic surgery or open surgery. Central randomisation was conducted using a web response system, and was stratified by clinical stage, age, sex, BMI, and American Society of Anesthesiologists classification. Investigators, patients and statisticians were not masked to group allocation. The primary outcome was 3-year disease-free survival, defined as the time from the date of surgery to the date of locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first. Non-inferiority was defined as a lower limit of one-sided 97·5% CI for group difference (laparoscopic surgery group minus open surgery group) of greater than -10%. The primary analyses were performed in the modified intention-to-treat population, which excluded patients with distant metastasis discovered during surgery and those who did not undergo surgery or underwent local resection only. The trial is registered with ClinicalTrials.gov, NCT01899547, and has been completed. Between Nov 12, 2013, and June 6, 2018, 1070 patients were enrolled and randomly assigned to treatment. 1039 patients (685 in the laparoscopic surgery group and 354 in the open surgery group; median age 57 years, IQR 50 to 64; 620 [60%] male and 419 [40%] women) were included in the modified intention-to-treat analysis. 3-year disease-free survival was 81·4% (95% CI 78·2 to 84·1) in the laparoscopic surgery group and 79·8% (75·2 to 83·6) in the open surgery group (hazard ratio [HR] 0·92, 95% CI 0·69 to 1·23; p=0·56). The difference between groups was 1·60% (one-sided 97·5% CI -3·34 to ∞, p<0·0001 for non-inferiority). 3-year overall survival was 91·7% (95% CI 89·3 to 93·5) in the laparoscopic surgery group and 93·7% (90·6 to 95·8) in the open surgery group (HR 1·34, 95% CI 0·82 to 2·19; p=0·24). 3-year locoregional recurrence was 3·7% (95% CI 2·5 to 5·3) and 2·3% (1·1 to 4·3), respectively (HR 1·64, 95% CI 0·74 to 3·63; p=0·22). 5-year overall survival was 84·6% (95% CI 81·5 to 87·1) and 86·6% (82·5 to 89·8) in the open group (HR 1·16, 95% CI 0·82 to 1·64; p=0·41). Laparoscopic surgery performed by experienced surgeons is non-inferior to open surgery for 3-year disease-free survival among patients with low rectal cancer. These results support the use of laparoscopic surgery for low rectal cancer. The Key Clinical Specialty Discipline Construction Program of the National Health and Family Planning Commission of China; Minimally Invasive Medical Center Construction Program, Fujian Province, China; and Joint Funds for the Innovation of Science and Technology, Fujian Province, China.

Teleconsultation on patients with type 2 diabetes in the Brazilian public health system: a randomised, pragmatic, open-label, phase 2, non-inferiority trial (TELECONSULTA diabetes trial)

This study addresses the rising burden of type 2 diabetes mellitus, and explores the potential of teleconsultation, as an alternative for diabetes management. The primary objective was to test the hypothesis that teleconsultation is non-inferior to face-to-face consultation in terms of glycaemic control measured as glycated haemoglobin (HbA1c) (non-inferiority margin for the upper confidence interval for the difference between groups of 0,5% in HbA1c) for type 2 diabetes mellitus patients referred from Primary Healthcare to Specialized Care within the SUS. TELECONSULTA, is a randomized, pragmatic, phase 2, single-centre, open-label, non-inferiority trial conducted in Joinville, Brazil. A total of 278 participants diagnosed with type 2 diabetes were randomized through mandatory teleconsulting services from primary care health units. The randomization was 1:1 to teleconsultation or face to face consultation. The study was registered at the Brazilian Clinical Trial Register-REBEC, under the code RBR-8gpgyd. Study status is "Completed". This study included 278 participants in the intention-to-treat (ITT) analysis. The median age was 61 (54-68) years, 167 (60%) were women. The between-groups comparative average reduction in HbA1c was-0.6% (90% CI-1.0;-0.1) at 3-months and-0.5% (90% CI-0.9; 0.0) at 6-months in Modified Intention-to-Treat (mITT) population with imputed data, showing the non-inferiority of teleconsultation. Results with no missing data imputation and in the per protocol population were similar. The frequency of hypoglycaemia and other adverse events was well balanced between groups. The results underscore the transformative potential of telemedicine in addressing the complexities of diabetes management within the framework of a universal healthcare system, contributing with valuable insights for healthcare policymakers and practitioners seeking innovative solutions to tackle the growing diabetes epidemic. This study was funded by the Brazilian Ministry of Health, through the Unified Health System-Institutional Development Support Program (PROADI-SUS).

Non-inferiority trial in veal calves on the efficacy of oxytetracycline and florfenicol treatment for pneumonia guided by quick thoracic ultrasound

Purchase dependent calf rearing systems, such as the white veal industry, systematically rely on antimicrobial mass medication (metaphylaxis) to counter respiratory tract infections. Despite mounting criticism, the industry fears that without metaphylaxis, mortality would drastically increase. This randomized clinical trial aimed to compare the efficacy of a quick thoracic ultrasonography (qTUS) individualized treatment length between oxytetracycline (OTC) and florfenicol (FF). Regression of maximum consolidation depth < 1cm was used as a criterion for cure and to stop antimicrobial treatment. Additionally, the study assessed the associations of consolidation depth at treatment initiation with cure and treatment duration. The trial involved 320 veal calves, randomly assigned into one of 2 groups: one receiving OTC (n = 160) and the other FF (n = 160) on d 1 (2-d metaphylaxis). Clinical scoring and qTUS were done on d 1 and every 48 h for a 10-d period. After d 1, only calves with consolidations ≥ 1cm were given further treatment. On each time point, maximum consolidation depth was used to categorize calves into 4 qTUS categories: healthy (no consolidation), mild pneumonia (consolidation < 1cm), moderate pneumonia (consolidation 1-3cm) and severe pneumonia (consolidation ≥ 3cm). Cure, treatment duration and the number of antimicrobial dosages (NAD) were compared between treatment groups. In addition, pathogen identification and antimicrobial susceptibility testing was performed on isolates from non-endoscopic broncho alveolar lavage fluid. On d 1, 30.0% (96/320) of the calves had consolidation ≥ 1cm, which increased to 50.9% (162/318) by d 9. After single metaphylactic treatment, cure was 20.9% (9/43) and 20.9% (9/43) in the OTC and FF group, respectively. Calves with severe pneumonia had lower odds to be cured after first treatment than calves with moderate pneumonia (Odds ratio (OR) = 0.17; 95% Confidence interval (CI): 0.04 - 0.63). By d 9, final cure of the initial cases was 27.9% in both the OTC- and FF-group. both groups, cure was similar at all observation points (P > 0.05). Overall, final cure of all calves with either moderate or severe pneumonia during the trial was 41.2% (52/102) and 19.0% (12/63), respectively (P = 0.004). Median treatment duration was 4 d (Interquartile range (IQR) = 2-6; Minimum (Min) = 2; Maximum (Max) = 8) and was similar in both treatment groups (P = 0.59). Treatment duration for calves with moderate pneumonia (Med = 6; IQR = 4-6; Min = 2; Max = 8) was lower than the median treatment duration of calves with severe pneumonia (Med = 8; IQR = 4-8; Min = 2; Max = 8) (P = 0.004). When compared with calves with mild pneumonia on d 1, calves with moderate (P = 0.01) and severe pneumonia (P < 0.001) had significantly longer treatment durations. In this study, cure was low and not different between both antimicrobials. Categorizing calves based on consolidation depth appears useful as both cure and treatment duration were different for the mild, moderate and severe group.

Comparison of Ultrasound-Guided Single-Injection Erector Spinae Plane Block, Retrolaminar Block and Paravertebral Block for Postoperative Analgesia in Single-Incision Video-Assisted Thoracoscopic Surgery: A Three-Arm, Double-Blind, Randomized Controlled Non-Inferiority Trial.

Effective postoperative analgesia is critical for thoracic surgery. This study compares the analgesic efficacy of the erector spinae plane block (ESPB), retrolaminar block (RLB), and paravertebral block (TPVB) in single-incision video-assisted thoracoscopic surgery (SITS). Seventy-six patients underwent general anesthesia followed by ultrasound-guided nerve blocks with 20mL of 0.5% ropivacaine. Primary outcomes included the area under the curve (AUC) of Numeric Rating Scale (NRS) scores during rest and coughing over 24 hours. Secondary outcomes included perioperative opioid use, plasma biomarkers, and postoperative recovery measures. The AUC for NRS was 107.8±10.53 in the ESPB group, 104.8±8.05 in the RLB group, and 103.6±10.42 in the TPVB group, demonstrating non-inferiority for ESPB (difference: 4.2±3.0, 95% CI -1.82 to 10.22) and RLB (difference: 1.2±2.6, 95% CI -3.97 to 6.37) compared to TPVB. No significant differences were observed in opioid use, plasma biomarkers, QoR-15 scores, or adverse events. ESPB and RLB provide non-inferior analgesia compared to TPVB in SITS patients and are effective alternatives that enhance safety.

Chewing gum to treat postoperative nausea and vomiting in female patients: a multicenter randomized trial.

Postoperative nausea and vomiting (PONV) is common after general anesthesia, with consequences for patient outcomes, satisfaction with care and healthcare costs. Our aim was to compare a new treatment, chewing gum, with a widely-used intravenous agent, ondansetron, to treat PONV in female patients in the post anesthesia care unit (PACU). We conducted a multicenter, randomized, controlled non-inferiority trial in 17 hospitals in Australia and New Zealand. Female patients aged ≥12 years undergoing volatile anesthetic-based general anesthesia for laparoscopic or breast surgery were enrolled. Protocolized anti-emetic prophylaxis was administered. Patients who developed PONV in the PACU were randomized to either 15 min of chewing gum or 4 mg of intravenous ondansetron. The primary outcome was cessation of nausea, retching or vomiting, with no recurrence nor rescue medication for 2 h after administration of the randomized intervention (i.e., complete response). Of 865 enrolled patients, 218 were randomized. In a per-protocol analysis, 50 of 105 (47.6%) ondansetron-treated patients compared with 31 of 103 (30.1%) chewing gum-treated patients achieved the primary outcome (absolute risk difference [95% confidence interval (CI)] -17.3 [-30.4 to -4.3] %), not reaching our prespecified non-inferiority limit. Time to complete response was longer for patients randomized to chewing gum (hazard ratio [95% CI] 0.53 [0.34, 0.83]), and they were more likely to receive antiemetics in the 24 h after surgery (absolute risk difference [95% CI] 14.07 [1.65, 26.49]). Chewing gum cannot be recommended as an alternative to ondansetron for treatment of PONV in female patients administered antiemetic prophylaxis.

Nociception level index-directed superficial parasternal intercostal plane block vs erector spinae plane block in open-heart surgery: a propensity matched non-inferiority clinical trial.

This single-center study explored the efficacy of superficial parasternal intercostal plane block (SPIPB) versus erector spinae plane block (ESPB) in opioid-sparing within Nociception Level (NOL) index-directed anesthesia for elective open-heart surgery. After targeted propensity matching, 19 adult patients given general anesthesia with preincisional SPIPB were compared to 33 with preincisional ESPB. We hypothesized that SPIPB is non-inferior to ESPB in reducing total intraoperative fentanyl consumption, with a non-inferiority margin (δ) set at 0.1mg. Intraoperative fentanyl dosing targeted a NOL index ≤ 25. Postoperatively, paracetamol 1g 6-hourly and morphine for numeric rating scale (NRS) ≥ 4 were administered. This study could not demonstrate that SPIPB was inferior to ESPB for total intraoperative fentanyl consumption, as the confidence interval for the median difference of 0.1mg (95% CI 0.05-0.15) crossed the predefined δ, with the lower bound falling below and the upper bound exceeding δ, p = 0.558. SPIPB led to higher postoperative morphine use at 24 and 48h: 0 (0-40.6) vs. 59.5 (28.5-96.1) µg kg-1, p < 0.001 and 22.2 (0-42.6) vs. 63.5 (28.5-96.1) µg kg-1, p = 0.001. Four times fewer SPIPB patients remained morphine-free at 48h, p < 0.001, and their time to first morphine dose was three times shorter compared to ESPB patients, p = 0.001. SPIPB led to higher time-weighted average NRS scores at rest, 1 (0-1) vs. 1 (1-2), p = 0.004, and with movement, 2 (1-2) vs. 3 (2-3), p = 0.002, calculated over the 48-h period post-extubation. The SPIPB group had a significantly higher average NOL index, p = 0.003, and greater NOL index variability, p = 0.027. This study could not demonstrate that SPIPB was inferior to ESPB for intraoperative fentanyl consumption. Significant differences were observed in secondary outcomes, with SPIPB leading to higher postoperative morphine use, higher pain scores, and reduced nociception control.

Equal performance of the subcutaneous and transvenous implantable cardioverter defibrillator across all age groups in the PRAETORIAN trial

Abstract Introduction The subcutaneous ICD (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. In the PRAETORIAN trial the S-ICD proved to be non-inferior to the TV-ICD with regard to inappropriate shocks (IAS) and complications. However, the S-ICD is still mainly the preferred choice in young patients with a long life expectancy and therefore higher risk for lead-related complications. We aimed to evaluate the impact of age on complications and IAS between the S-ICD and TV-ICD. Methods The PRAETORIAN trial is an investigator-initiated, international, multicenter, randomized, two-arm noninferiority trial that was conducted in the United States and Europe. In total 849 patients with a class I or IIa indication for ICD therapy and no pacing indication were randomized to receive an S-ICD (N=426) or TV-ICD (N=423) and followed for a median of 49 months. We compare the occurrence of complications and IAS between increasing quartiles of age. Results Quartile 1 (Q1) consisted of 203 patients aged &amp;lt;55 (109 S-ICD, 94 TV-ICD), Q2 of 199 patients aged 55-62 (100 S-ICD, 99 TV-ICD), Q3 of 232 patients aged 63-69 (111 S-ICD, 121 TV-ICD) and Q4 of 215 patients aged ≥70 (106 S-ICD, 109 TV-ICD). Between the quartiles, there were no significant differences in occurrence of device-related complications (P = 0.32) or IAS (P = 0.66). In Q1, there were 15 (7.4%) complications (5 S-ICD, 10 TV-ICD) and 13 (6.4%) IAS (7 S-ICD, 6 TV-ICD), compared to 20 (10.1%) complications (7 S-ICD, 13 TV-ICD) and 17 (8.5%) IAS (9 S-ICD, 8 TV-ICD) in Q2, 22 (9.5%) complications (12 S-ICD, 10 TV-ICD) and 19 (8.2%) IAS (11 S-ICD, 8 TV-ICD) in Q3 and 18 (8.4%) complications (7 S-ICD, 11 TV-ICD) and 21 (9.8%) IAS (14 S-ICD, 7 TV-ICD) in Q4 (Figure 1.). Figure 2. shows forest plots of the hazard ratios per quartile. Conclusions The S-ICD performed equal to the TV-ICD with regard to IAS and complications between quartiles of age, making the S-ICD a good alternative across all age groups.