Sex-Based Analysis of Workflow and Outcomes in Acute Ischemic Stroke Patients Treated With Alteplase Versus Tenecteplase.

BACKGROUND: Understanding sex differences in stroke care is important in reducing potential disparities. Our objective was to explore sex differences in workflow efficiency, treatment efficacy, and safety in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: AcT was a multicenter, registry-linked randomized noninferiority trial comparing tenecteplase (0.25 mg/kg) with alteplase (0.9 mg/kg) in acute ischemic stroke within 4.5 hours of onset. In this post hoc analysis, baseline characteristics, workflow times, successful reperfusion (extended Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracerebral hemorrhage, 90-day functional independence (modified Rankin Scale score, 0-1), and 90-day mortality were compared by sex. Mixed-effects regression analysis was used adjusting for age, stroke severity, and occlusion site for outcomes. RESULTS: Of 1577 patients treated with intravenous thrombolysis (2019-2022), 755 (47.9%) were women. Women were older (median, 77 [68-86] years in women versus 70 [59-79] years in men) and had a higher proportion of severe strokes (National Institutes of Health Stroke Scale score >15; 32.4% versus 24.9%) and large vessel occlusions (28.7% versus 21.5%) compared with men. All workflow times were comparable between sexes. Women were less likely to achieve functional independence (31.7% versus 39.8%; unadjusted relative risk, 0.80 [95% CI, 0.70-0.91]) and had higher mortality (17.7% versus 13.3%; unadjusted relative risk, 1.33 [95% CI, 1.06-1.69]). Adjusted analysis showed no difference in outcomes between sexes. CONCLUSIONS: Differences in prognostic factors of age, stroke severity, and occlusion site largely accounted for higher functional dependence and mortality in women. No sex disparities were apparent in workflow quality indicators. Given the integration of the AcT trial into clinical practice, these results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Canadian centers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Different dose aspirin plus immunoglobulin (DAPI) for prevention of coronary artery abnormalities in Kawasaki disease: Study protocol for a multi-center, prospective, randomized, open-label, blinded end-point, non-inferiority trial.

BACKGROUND: Kawasaki disease is a pediatric acute systemic vasculitis that specifically involves the coronary arteries. Timely initiation of immunoglobulin plus aspirin is necessary for diminishing the incidence of coronary artery abnormalities (CAAs). The optimal dose of aspirin, however, remains controversial. The trial aims to evaluate if low-dose aspirin is noninferior to moderate-dose in reducing the risk of CAAs during the initial treatment of Kawasaki disease. METHODS: This is a multi-center, prospective, randomized, open-label, blinded endpoint, noninferiority trial to be conducted in China. The planned study duration is from 2023 to 2026. Data will be analyzed according to intention-to-treat principles. Participants are children and adolescents under the age of 18 with Kawasaki disease, recruited from the inpatient units. A sample size of 1,346 participants will provide 80% power with a one-sided significance level of 0.025. Qualifying children will be randomized (1:1) to receive either intravenous immunoglobulin (2 g/kg) plus oral moderate-dose aspirin (30-50 mg·kg-1·d-1) until the patient is afebrile for at least 48 hours, or immunoglobulin plus low-dose aspirin (3-5 mg·kg-1·d-1) as initial treatment. The primary outcome will be the occurrence of CAAs at 8 weeks after immunoglobulin infusion. Independent blinded pediatric cardiologists will assess the primary endpoint using echocardiography. CONCLUSIONS: There is a shortage of consensus on the dose of aspirin therapy for Kawasaki disease due to the lack of evidence. The results of our randomized trial will provide more concrete evidence for the efficacy and adverse events of low- or moderate-dose aspirin in the acute phase of Kawasaki disease. TRIAL REGISTRATION: www.chictr.org.cn: ChiCTR2300072686.

Single vs. multiple fraction non-inferiority trial of stereotactic ablative radiotherapy for the comprehensive treatment of oligo-metastases/progression: SIMPLIFY-SABR-COMET.

BACKGROUND: Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience. METHODS: This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival. DISCUSSION: This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with inoperable esophageal squamous cell carcinoma: a multicenter non-inferiority phase III randomized clinical trial.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.

PET-CT-guided, symptom-based, patient-initiated surveillance versus clinical follow-up in head neck cancer patients (PETNECK2): study protocol for a multicentre feasibility study and non-inferiority, randomised, phase III trial.

BACKGROUND: Approximately 40% of treated head and neck cancer (HNC) patients develop recurrence. The risk of recurrence declines with time from treatment. Current guidelines recommend clinical follow-up every two months for the first two years after treatment, with reducing intensity over the next three years. However, evidence for the effectiveness of these regimes in detecting recurrence is lacking, with calls for more flexible, patient-centred follow-up strategies. METHODS: PETNECK2 is a UK-based multi-centre programme examining a new paradigm of follow-up, using positron emission tomography-computed tomography (PET-CT)-guided, symptom-based, patient-initiated surveillance. This paradigm is being tested in a unblinded, non-inferiority, phase III, randomised controlled trial (RCT). Patients with HNC, one year after completing curative intent treatment, with no clinical symptoms or signs of loco-regional or distant metastasis will be randomised using a 1:1 allocation ratio to either regular scheduled follow-up, or to PET-CT guided, patient-initiated follow-up. Patients at a low risk of recurrence (negative PET-CT) will receive a face-to-face education session along with an Information and Support (I&S) resource package to monitor symptoms and be in control of initiating an urgent appointment when required. The primary outcome of the RCT is overall survival. The RCT also has an in-built pilot, a nested QuinteT Recruitment Intervention (QRI), and a nested mixed-methods study on patient experience and fear of cancer recurrence (FCR). An initial, single-arm feasibility study has been completed which determined the acceptability of the patient-initiated surveillance intervention, the completion rates of baseline questionnaires, and optimised the I&S resource prior to implementation in the RCT. DISCUSSION: We hypothesise that combining an additional 12-month post-treatment PET-CT scan and I&S resource will both identify patients with asymptomatic recurrence and identify those at low risk of future recurrence who will be empowered to monitor their symptoms and seek early clinical follow-up when recurrence is suspected. This change to a patient-centred model of care may have effects on both quality of life and fear of cancer recurrence. TRIAL REGISTRATION: ISRCTN: 13,709,798; 15-Oct-2021.

Assessing efficacy in non-inferiority trials with non-adherence to interventions: Are intention-to-treat and per-protocol analyses fit for purpose?

BACKGROUND: Non-inferiority trials comparing different active drugs are often subject to treatment non-adherence. Intention-to-treat (ITT) and per-protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non-adherence. METHODS: The REMoxTB trial evaluated two 4-month experimental regimens compared with a 6-month control regimen for newly diagnosed drug-susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post-randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non-adherence in non-inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse-probability-of-treatment weighting (IPTW), and a doubly-robust (DR) estimator. RESULTS: When non-adherence differed between trial arms, ITT, and PP analyses often resulted in non-trivial bias in the estimated treatment effect, which consequently under- or over-inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non-adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power. CONCLUSIONS: When non-adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches.

Noninferiority trials in acute pain research: a valid approach or a slippery slope?

The conduct and reporting of studies with a noninferiority hypothesis is challenging because of the complexity involved in their design and interpretation. However, studies with a noninferiority design have increased in popularity. A recently published trial reported on the noninferiority of lidocaine infusion to epidural analgesia in major abdominal surgeries. Apart from needing a critical appraisal, this draws attention to improve our understanding of noninferiority study framework and its unique features. Given the increasing focus on using various analgesic adjuncts and multiple approaches to fascial plane blocks to avoid more definitive and standard approaches, it is imperative that particular attention is paid to appropriate execution and reporting of noninferiority studies.

Randomized evaluation of 5-month Ticagrelor monotherapy after 1-month dual-antiplatelet therapy in patients with acute coronary syndrome treated with drug-coated balloons: REC-CAGEFREE II trial rationale and design.

BACKGROUND: Patients treated with drug-coated balloons (DCB) have the theoretical advantage of adopting a low-intensity antiplatelet regimen due to the absence of struts and polymers. Nevertheless, the optimal antiplatelet strategy for patients undergoing DCB-only treatment remains a topic of debate and has not been investigated in randomized trials. METHODS: The REC-CAGEFREE II is an investigator-initiated, prospective, open-label, multi-center, randomized, non-inferiority trial aimed to enroll 1908 patients from ≥ 40 interventional cardiology centers in China to evaluate the non-inferiority of an antiplatelet regimen consisting of Aspirin plus Ticagrelor for one month, followed by five months Ticagrelor monotherapy, and then Aspirin monotherapy for six months (Experimental group) compared to the conventional treatment of Aspirin plus Ticagrelor for 12 months (Reference group) in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) using paclitaxel-coated balloons (DCB) exclusively. Participants will be randomly assigned to the Experimental or Reference group in a 1:1 ratio. The randomization will be stratified based on the center and the type of lesion being treated (De novo or in-stent restenosis). The primary endpoint is net adverse clinical events (NACE) within 12 months of PCI, which includes the composite of all-cause death, any stroke, any myocardial infarction, any revascularization and Bleeding Academic Research Consortium (BARC) defined type 3 or 5 bleeding. The secondary endpoint, any ischemic and bleeding event, which includes all-cause death, any stroke, MI, BARC-defined type 3 bleeding, any revascularization, and BARC-defined type 2 bleeding events, will be treated as having hierarchical clinical importance in the above order and analyzed using the win ratio method. DISCUSSION: The ongoing REC-CAGEFREE II trial aims to assess the efficacy and safety of a low-intensity antiplatelet approach among ACS patients with DCB. If non-inferiority is shown, the novel antiplatelet approach could provide an alternative treatment for ACS patients with DCB. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04971356.

Drug-coated balloon angioplasty with provisional stenting versus primary stenting for the treatment of de novo coronary artery lesions: REC-CAGEFREE I trial rationale and design.

BACKGROUND: Percutaneous coronary intervention (PCI) with primary stenting, which stands for stent implantation regardless of obtaining satisfactory results with balloon angioplasty, has superseded conventional plain old balloon angioplasty with provisional stenting. With drug-coated balloon (DCB), primary DCB angioplasty with provisional stenting has shown non-inferiority to primary stenting for de novo coronary small vessel disease. However, the long-term efficacy and safety of such a strategy to the primary stenting on clinical endpoints in de novo lesions without vessel diameter restrictions remain uncertain. STUDY DESIGN: The REC-CAGEFREE I is an investigator-initiated, multicenter, randomized, open-label trial aimed to enroll 2270 patients with acute or chronic coronary syndrome from 43 interventional cardiology centers in China to evaluate the non-inferiority of primary paclitaxel-coated balloons angioplasty to primary stenting for the treatment of de novo, non-complex lesions without vessel diameter restrictions. Patients who fulfill all the inclusion and exclusion criteria and have achieved a successful lesion pre-dilatation will be randomly assigned to the two arms in a 1:1 ratio. Protocol-guided DCB angioplasty and bailout stenting after unsatisfactory angioplasty are mandatory in the primary DCB angioplasty group. The second-generation sirolimus-eluting stent will be used as a bailout stent in the primary DCB angioplasty group and the treatment device in the primary stenting group. The primary endpoint is the incidence of Device-oriented Composite Endpoint (DoCE) within 24 months after randomization, including cardiac death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularization. DISCUSSION: The ongoing REC-CAGEFREE I trial is the first randomized trial with a clinical endpoint to assess the efficacy and safety of primary DCB angioplasty for the treatment of de novo, non-complex lesions without vessel diameter restrictions. If non-inferiority is shown, PCI with primary DCB angioplasty could be an alternative treatment option to primary stenting. TRIAL REGISTRATION: Registered on clinicaltrial.gov (NCT04561739).

Protocol of the LATFIA trial (Laser Assisted Treatment of Fistula in Ano): a multicentre, prospective, randomized controlled trial comparing fistula-tract laser closure (FiLaC™) with rectal advancement flap for high trans-sphincteric fistulas.

AIM: Anal fistula is one of the most common anal diseases, affecting between 1 and 3 per 10 000 people per year. Symptoms have a potentially severe effect on a patient's quality of life. Surgery is the mainstay of treatment, aiming to cure the fistula and preserve anal sphincter function. Rectal advancement flap (RAF) is currently the gold standard treatment but has recurrence rates varying between 20% and 50% and might lead to disturbance of continence. The aim of the trial described in this work is to discover if the minimally invasive fistula tract laser closure (FiLaC™) technique could achieve higher healing rates and a better functional outcome than RAF. METHOD: We will perform a randomized prospective multicentre noninferiority study of the treatment of high trans-sphincteric perianal fistulas, comparing FiLaC™ with RAF in terms of fistula healing, recurrence rate, functional outcome and quality of life. Primary and secondary fistula healing will be evaluated at 26 and 52 weeks' follow-up. Quality of life will be evaluated using the SF-36 questionnaire, the Faecal Incontinence Quality of Life Scale questionnaire and the Vaizey score at 3, 6, 12 and 26 weeks postoperatively. CONCLUSION: High trans-sphincteric fistulas have a potentially severe effect on a patient's quality of life. Classical treatment with RAF is a time-consuming invasive procedure. The LATFIA trial aims to compare FiLaC™ with the gold standard treatment with RAF. In case of noninferiority, FiLaC™ treatment could be standardized as a first line treatment for high trans-sphincteric fistulas. Better conservation of the patient's anal sphincter function could possibly be obtained. Likewise, we will report on the postoperative quality of life when applying these two techniques.

Is mechanical bowel preparation necessary to reduce surgical site infection following colon surgery? Protocol for a multicentre Canadian randomized controlled trial.

AIM: There is significant practice variation with respect to the use of bowel preparation to reduce surgical site infection (SSI) following colon surgery. Although intravenous antibiotics + mechanical bowel preparation + oral antibiotics (IVA + MBP + OA) has been shown to be superior to IVA + MBP and IVA, there are insufficient high-quality data from randomized controlled trails (RCTs) that directly compare these options. This is an important question, because if IVA + OA has similar effectiveness to IVA + MBP + OA, mechanical bowel preparation can be safely omitted, and the associated side effects avoided. The aim of this work is to compare rates of SSI following IVA + OA + MBP (MBP) versus IVA + OA (OA) for elective colon surgery. METHOD: This is a multicentre, parallel, two-arm, noninferiority RCT comparing IVA + OA + MBP versus IVA + OA. The primary outcome is the overall rate of SSI 30 days following surgery. Secondary outcomes are length of stay and 30-day emergency room visit and readmission rates. The planned sample size is 1062 subjects with four participating high-volume centres. Overall SSI rates 30 days following surgery between the treatment groups will be compared using a general linear model. Secondary outcomes will be analysed with linear regression for continuous outcomes, logistic regression for binary outcomes and modified Poisson regression for count data. CONCLUSION: It is expected that IVA + OA will work similarly to IVA + MBP + OA and that this work will provide definitive evidence showing that MBP is not necessary to reduce SSI. This is highly relevant to both patients and physicians as it will have the potential to significantly change practice and outcomes following colon surgery in Canada and beyond.

Non-inferiority trials with time-to-event data: clarifying the impact of censoring.

In non-inferiority (NI) trials with time-to-event data, different types and patterns of censoring may occur, but their impact on trial results is not entirely clear. We investigated the influence of informative and non-informative censoring by conducting extensive simulation studies under the assumption that the NI margin is defined as a maximum acceptable hazard ratio and scenarios typically observed in recent NI trials. We found that while non-informative censoring tends to only affect the power, informative censoring can impact the treatment effect estimates, type I error rate, and power. The magnitude of these effects depends on the between-group differences in the failure and informative censoring risks, as well as the correlation between censoring and failure times, among other factors. The adverse impact of informative censoring was generally decreased with larger NI margins.

Treatment outcomes of pulpotomy versus pulpectomy in vital primary molars diagnosed with symptomatic irreversible pulpitis: protocol for a non-inferiority randomised controlled trial.

BACKGROUND: Pulpectomy continues to be the standard treatment recommendation for management of vital primary molars diagnosed with symptomatic irreversible pulpitis. The recent decade has seen a paradigm shift in the treatment concepts of how vital mature permanent molars diagnosed with irreversible pulpitis can be more conservatively managed using vital pulp therapy techniques like pulpotomy. However, despite emerging evidence indicating similarities between primary and permanent tooth pulp response to dental caries, there is limited research on whether pulpotomy can be similarly used as a definitive treatment modality for vital primary teeth with irreversible pulpitis. This randomised controlled trial (RCT) aims to compare the treatment effectiveness of pulpotomy versus pulpectomy in management of vital primary molars diagnosed with symptomatic irreversible pulpitis over a two-year period. METHODS/DESIGN: This clinical study is a parallel, two-armed, open label, non-inferiority RCT with a 1:1 allocation ratio between the experimental intervention arm (pulpotomy) and the active comparator arm (pulpectomy). Healthy cooperative children, between 4-9 years of age, who have painful primary molars with clinical symptoms typical of irreversible pulpitis will be recruited after obtaining informed consent from their parents/legal guardians. 50 vital primary molars clinically diagnosed with symptomatic irreversible pulpitis will be randomly distributed between the two treatment arms. The primary outcomes that will be assessed are clinical and radiographic success after six-months, one-year and two-years of the trial interventions. The influence of baseline pre-operative variables (age; gender; tooth type; site of caries; pre-operative furcal radiolucency; pre-operative pain intensity) and intra-operative factors (time taken to achieve haemostasis) on treatment outcomes will also be assessed. The secondary outcome evaluated will be the immediate (24 h and 7 d) post-operative pain relief afforded by the two treatment interventions. DISCUSSION: This trial seeks to provide evidence on whether pulpotomy treatment can be no worse than the standard pulpectomy treatment for the management of symptomatic irreversible pulpitis in vital primary molars. TRIAL REGISTRATION: ClinicalTrials.gov (NCT06183203). Registered on 30 January 2024.

Commentary on 2022 guidelines on clinical trial design in cluster headache and further suggestions.

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies. MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment. CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

Cost-effectiveness of 5 fraction and partial breast radiotherapy for early breast cancer in the UK: model-based multi-trial analysis.

PURPOSE: We estimated the cost-effectiveness of 4 radiotherapy modalities to treat early breast cancer in the UK. In a subgroup of patients eligible for all modalities, we compared whole-breast (WB) and partial breast (PB) radiotherapy delivered in either 15 (WB15F, PB15F) or 5 fractions (WB5F, PB5F). In a subgroup ineligible for PB radiotherapy, we compared WB15F to WB5F. METHODS: We developed a Markov cohort model to simulate lifetime healthcare costs and quality-adjusted life years (QALYs) for each modality. This was informed by the clinical analysis of two non-inferiority trials (FAST Forward and IMPORT LOW) and supplemented with external literature. The primary analysis assumed that radiotherapy modality influences health only through its impact on locoregional recurrence and radiotherapy-related adverse events. RESULTS: In the primary analysis, PB5F had the least cost and greatest expected QALYs. WB5F had the least cost and the greatest expected QALYs in those only eligible for WB radiotherapy. Applying a cost-effectiveness threshold of £15,000/QALY, there was a 62% chance that PB5F was the cost-effective alternative in the PB eligible group, and there was a 100% chance that WB5F was cost-effective in the subgroup ineligible for PB radiotherapy. CONCLUSIONS: Hypofractionation to 5 fractions and partial breast radiotherapy modalities offer potentially important benefits to the UK health system.

Exact-corrected confidence interval for risk difference in noninferiority binomial trials.

A novel confidence interval estimator is proposed for the risk difference in noninferiority binomial trials. The proposed confidence interval, which is dependent on the prespecified noninferiority margin, is consistent with an exact unconditional test that preserves the type-I error and has improved power, particularly for smaller sample sizes, compared to the confidence interval by Chan and Zhang. The improved performance of the proposed confidence interval is theoretically justified and demonstrated with simulations and examples. An R package is also distributed that implements the proposed methods along with other confidence interval estimators.

Practical approaches to Bayesian sample size determination in non-inferiority trials with binary outcomes.

Bayesian analysis of a non-inferiority trial is advantageous in allowing direct probability statements to be made about the relative treatment difference rather than relying on an arbitrary and often poorly justified non-inferiority margin. When the primary analysis will be Bayesian, a Bayesian approach to sample size determination will often be appropriate for consistency with the analysis. We demonstrate three Bayesian approaches to choosing sample size for non-inferiority trials with binary outcomes and review their advantages and disadvantages. First, we present a predictive power approach for determining sample size using the probability that the trial will produce a convincing result in the final analysis. Next, we determine sample size by considering the expected posterior probability of non-inferiority in the trial. Finally, we demonstrate a precision-based approach. We apply these methods to a non-inferiority trial in antiretroviral therapy for treatment of HIV-infected children. A predictive power approach would be most accessible in practical settings, because it is analogous to the standard frequentist approach. Sample sizes are larger than with frequentist calculations unless an informative analysis prior is specified, because appropriate allowance is made for uncertainty in the assumed design parameters, ignored in frequentist calculations. An expected posterior probability approach will lead to a smaller sample size and is appropriate when the focus is on estimating posterior probability rather than on testing. A precision-based approach would be useful when sample size is restricted by limits on recruitment or costs, but it would be difficult to decide on sample size using this approach alone.

Natural orifice specimen extraction surgery versus small-incision assisted laparoscopic radical right hemicolectomy.

Conventional laparoscopic-assisted right hemicolectomy requires a small abdominal incision to extract the specimen, which becomes an important source of postoperative complications and impairs perioperative experience. Transvaginal natural orifice specimen extraction surgery (NOSES VIIIA) avoids this small incision by extracting the specimen through the vagina. Here we describe the design of a multicenter, open-label, parallel, noninferior, phase III randomized controlled trial (NCT05495048). The aim of this study is to confirm that the NOSES VIIIA procedure is not inferior to small-incision assisted right hemicolectomy in long-term oncological efficacy. A total of 352 female patients with right colon adenocarcinoma/high-grade intraepithelial neoplasia will be randomly assigned to the NOSES VIIIA arm and the small-incision arm in a 1:1 ratio. The primary end point of this trial is 3 year disease-free survival. Clinical Trial Registration: NCT05495048 (ClinicalTrials.gov).

GRECCAR 14 - a multicentric, randomized, phase II-III study evaluating the tailored management of locally advanced rectal carcinoma after a favourable response to induction chemotherapy: Study protocol.

AIM: Total neoadjuvant treatment (TNT) is becoming standard in patients with locally advanced rectal carcinoma (LARC). Preoperative chemoradiotherapy (CRT) has proven side effects on bowel and genitourinary function. An early tumoral response to induction chemotherapy demonstrates its high prognostic value. Tailored management could be used as an alternative to systematic CRT. The GRECCAR 14 trial will attempt to personalize treatment strategy according to the patient's early tumour response to intensive chemotherapy with the aim of achieving the best toxicity-efficiency ratio. METHOD: GRECCAR 14 is a multicentric, randomized, two-arm, phase II-III noninferiority trial. Patients with mid or low LARC with a predictive circumferential resection margin ≤2 mm or T3c-d stage with extramural venous invasion will be included. Evaluation of the tumoral response will be performed after six courses of high-dose FOLFIRINOX chemotherapy. Good responders (GRs) will be defined by a 60% decrease in tumoral volume on magnetic resonance imaging. Patients will be randomized to CRT before surgery. The primary endpoints will be R0 resection for phase II and the 3-year disease-free survival (DFS) for phase III. RESULTS: Tailored management of LARC is becoming an exciting challenge for the modality of neoadjuvant treatment and for the type of surgery or its omission. Neoadjuvant FOLFIRINOX has established efficacy, with a significant increase in the 3-year DFS. Better control of systemic disease must be accompanied by the same locoregional control, with the lowest morbidity. Our previous GRECCAR 4 trial demonstrated the high value of the early tumoral response after induction chemotherapy and the long-term safety of tailored management for GRs. CONCLUSION: If GRECCAR 14 demonstrates the ability to tailor TNT for LARC, this could lead to changes in clinical practice.

Handling intercurrent events and missing data in non-inferiority trials using the estimand framework: A tuberculosis case study.

INTRODUCTION: The ICH E9 addendum outlining the estimand framework for clinical trials was published in 2019 but provides limited guidance around how to handle intercurrent events for non-inferiority studies. Once an estimand is defined, it is also unclear how to deal with missing values using principled analyses for non-inferiority studies. METHODS: Using a tuberculosis clinical trial as a case study, we propose a primary estimand, and an additional estimand suitable for non-inferiority studies. For estimation, multiple imputation methods that align with the estimands for both primary and sensitivity analysis are proposed. We demonstrate estimation methods using the twofold fully conditional specification multiple imputation algorithm and then extend and use reference-based multiple imputation for a binary outcome to target the relevant estimands, proposing sensitivity analyses under each. We compare the results from using these multiple imputation methods with those from the original study. RESULTS: Consistent with the ICH E9 addendum, estimands can be constructed for a non-inferiority trial which improves on the per-protocol/intention-to-treat-type analysis population previously advocated, involving respectively a hypothetical or treatment policy strategy to handle relevant intercurrent events. Results from using the 'twofold' multiple imputation approach to estimate the primary hypothetical estimand, and using reference-based methods for an additional treatment policy estimand, including sensitivity analyses to handle the missing data, were consistent with the original study's reported per-protocol and intention-to-treat analysis in failing to demonstrate non-inferiority. CONCLUSIONS: Using carefully constructed estimands and appropriate primary and sensitivity estimators, using all the information available, results in a more principled and statistically rigorous approach to analysis. Doing so provides an accurate interpretation of the estimand.