After stent implantation for ACS, ticagrelor monotherapy after <1 mo of DAPT vs. 12 mo of DAPT improved 1-y net clinical benefit.

SOURCE CITATION: Hong SJ, Lee SJ, Suh Y, et al; T-PASS (Ticagrelor Monotherapy in Patients Treated With New-Generation Drug-Eluting Stents for Acute Coronary Syndrome) Investigators. Stopping aspirin within 1 month after stenting for ticagrelor monotherapy in acute coronary syndrome: the T-PASS randomized noninferiority trial. Circulation. 2024;149:562-573. 37878786.

The tyranny of non-inferiority trials.

Opportunities to decrease the toxicity and cost of approved treatment regimens with lower dose, less frequent, or shorter duration alternative regimens have been limited by the perception that alternatives must be non-inferior to approved regimens. Non-inferiority trials are large and expensive to do, because they must show statistically that the alternative and approved therapies differ in a single outcome, by a margin far smaller than that required to demonstrate superiority. Non-inferiority's flaws are manifest: it ignores variability expected to occur with repeated evaluation of the approved therapy, fails to recognise that a trial of similar design will be labelled as superiority or non-inferiority depending on whether it is done prior to or after initial registration of the approved treatment, and relegates endpoints such as toxicity and cost. For example, while a less toxic and less costly regimen of 3 months duration would typically be required to demonstrate efficacy that is non-inferior to that of a standard regimen of 6 months to displace it, the longer duration therapy has no such obligation to prove its superiority. This situation is the tyranny of the non-inferiority trial: its statistics perpetuate less cost-effective regimens, which are not patient-centred, even when less intensive therapies confer survival benefits nearly identical to those of the standard, by placing a disproportionately large burden of proof on the alternative. This approach is illogical. We propose that the designation of trials as superiority or non-inferiority be abandoned, and that randomised, controlled trials should henceforth be described simply as "comparative".

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.

Fully automated quantitative coronary angiography versus optical coherence tomography guidance for coronary stent implantation (FLASH): Study protocol for a randomized controlled noninferiority trial.

BACKGROUND: Artificial intelligence-based quantitative coronary angiography (AI-QCA) has been developed to provide a more objective and reproducible data about the severity of coronary artery stenosis and the dimensions of the vessel for intervention in real-time, overcoming the limitations of significant inter- and intraobserver variability, and time-consuming nature of on-site QCA, without requiring extra time and effort. Compared with the subjective nature of visually estimated conventional CAG guidance, AI-QCA guidance provides a more practical and standardized angiography-based approach. Although the advantage of intravascular imaging-guided PCI is increasingly recognized, their broader adoption is limited by clinical and economic barriers in many catheterization laboratories. METHODS: The FLASH (fully automated quantitative coronary angiography versus optical coherence tomography guidance for coronary stent implantation) trial is a randomized, investigator-initiated, multicenter, open-label, noninferiority trial comparing the AI-QCA-assisted PCI strategy with optical coherence tomography-guided PCI strategy in patients with significant coronary artery disease. All operators will utilize a novel, standardized AI-QCA software and PCI protocol in the AI-QCA-assisted group. A total of 400 patients will be randomized to either group at a 1:1 ratio. The primary endpoint is the minimal stent area (mm2), determined by the final OCT run after completion of PCI. Clinical follow-up and cost-effectiveness evaluations are planned at 1 month and 6 months for all patients enrolled in the study. RESULTS: Enrollment of a total of 400 patients from the 13 participating centers in South Korea will be completed in February 2024. Follow-up of the last enrolled patients will be completed in August 2024, and primary results will be available by late 2024. CONCLUSION: The FLASH is the first clinical trial to evaluate the feasibility of AI-QCA-assisted PCI, and will provide the clinical evidence on AI-QCA assistance in the field of coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT05388357.

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.

Non-Inferiority Trials: A Systematic Review on Methodological Quality and Reporting Standards.

BACKGROUND: Non-inferiority (NI) trials require unique trial design and methods, which pose challenges in their interpretation and applicability, risking introduction of inferior therapies in clinical practice. With the abundance of novel therapies, NI trials are increasing in publication. Prior studies found inadequate quality of reporting of NI studies, but were limited to certain specialties/journals, lacked NI margin evaluation, and did not examine temporal changes in quality. We conducted a systematic review without restriction to journal type, journal impact factor, disease state or intervention to evaluate the quality of NI trials, including a comprehensive risk of bias assessment and comparison of quality over time. METHODOLOGY: We searched PubMed and Cochrane Library databases for NI trials published in English in 2014 and 2019. They were assessed for: study design and NI margin characteristics, primary results, and risk of bias for blinding, concealment, analysis method and missing outcome data. RESULTS: We included 823 studies. Between 2014 and 2019, a shift from publication in specialty to general journals (15% vs 28%, p < 0.001) and from pharmacological to non-pharmacological interventions (25% vs 38%, p = 0.025) was observed. The NI margin was specified in most trials for both years (94% vs 95%). Rationale for the NI margin increased (36% vs 57%, p < 0.001), but remained low, with clinical judgement the most common rationale (30% vs 23%), but more 2019 articles incorporating patient values (0.3% vs 21%, p < 0.001). Over 50% of studies were open-label for both years. Gold standard method of analyses (both per protocol + (modified) intention to treat) declined over time (43% vs 36%, p < 0.001). DISCUSSION: The methodological quality and reporting of NI trials remains inadequate although improving in some areas. Improved methods for NI margin justification, blinding, and analysis method are warranted to facilitate clinical decision-making.

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.

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.

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.

Evaluating the effectiveness of a multi-component lifestyle therapy program versus psychological therapy for managing mood disorders (HARMON-E): protocol of a randomised non-inferiority trial.

BACKGROUND: Mood disorders, including unipolar and bipolar depression, contribute significantly to the global burden of disease. Psychological therapy is considered a gold standard non-pharmacological treatment for managing these conditions; however, a growing body of evidence also supports the use of lifestyle therapies for these conditions. Despite some clinical guidelines endorsing the application of lifestyle therapies as a first-line treatment for individuals with mood disorders, there is limited evidence that this recommendation has been widely adopted into routine practice. A key obstacle is the insufficient evidence on whether lifestyle therapies match the clinical and cost effectiveness of psychological therapy, particularly for treating those with moderate to severe symptoms. The HARMON-E Trial seeks to address this gap by conducting a non-inferiority trial evaluating whether a multi-component lifestyle therapy program is non-inferior to psychological therapy on clinical and cost-effectiveness outcomes over 8-weeks for adults with major depressive disorder and bipolar affective disorder. METHODS: This trial uses an individually randomised group treatment design with computer generated block randomisation (1:1). Three hundred and seventy-eight adults with clinical depression or bipolar affective disorder, a recent major depressive episode, and moderate-to-severe depressive symptoms are randomised to receive either lifestyle therapy or psychological therapy (adjunctive to any existing treatments, including pharmacotherapies). Both therapy programs are delivered remotely, via a secure online video conferencing platform. The programs comprise an individual session and six subsequent group-based sessions over 8-weeks. All program aspects (e.g. session duration, time of day, and communications between participants and facilitators) are matched except for the content and program facilitators. Lifestyle therapy is provided by a dietitian and exercise physiologist focusing on four pillars of lifestyle (diet, physical activity, sleep, and substance use), and the psychological therapy program is provided by two psychologists using a cognitive behavioural therapy approach. Data collection occurs at baseline, 8-weeks, 16-weeks, and 6 months with research assistants blinded to allocation. The primary outcome is depressive symptoms at 8 weeks, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) (minimal clinically important difference = 1.6). A pre-specified within-trial economic evaluation will also be conducted. DISCUSSION: Should lifestyle therapy be found to be as clinically and cost effective as psychological therapy for managing mood disorders, this approach has potential to be considered as an adjunctive treatment for those with moderate to severe depressive symptoms. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12622001026718, registered 22nd July 2022. PROTOCOL VERSION:  4.14, 26/06/2024.

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.

Breaking the cycle of reoccurring low back pain with integrated motivational interviewing and cognitive behavioural therapy to facilitate education and exercise advice: a superiority randomised controlled trial study protocol.

BACKGROUND: Non-specific low back pain is a common and costly global issue. Many people with low back pain live for years with ongoing symptom recurrence and disability, making it crucial to find effective prevention strategies. Motivational interviewing (MI) is an evidence-based patient-centred counselling style that helps motivate individuals to change their behaviours. In combination, MI and cognitive-behavioural therapy (MI-CBT) has the potential to yield long term improvements in pain and disability and reduce incidence of recurrence. METHOD: This is a two-arm superiority randomised controlled trial comparing MI-CBT and Education (n = 83) with Education only (n = 83). Participants that have recovered from a recent episode of non-specific low back pain (7th consecutive day with pain ≤ 2 on a 0-10 numeric pain rating scale) will be eligible for inclusion into the study. Both groups will receive five 30-min sessions over a 10-week period as well as the Navigating Pain booklet, homework book and a standardised exercise programme. In the intervention group, MI-CBT techniques will be used to provide individualised support, identify beliefs, and increase engagement with the resources provided. Outcomes measures include pain (current and in the last 7 days) as rated on the numeric pain rating scale. This will be used to determine recurrence (number of participants who report back pain ≥ 3 out of 10 on the numeric pain rating scale). Furthermore, self-reported (1) pain intensity; (2) pain catastrophizing; (3) fear-avoidance beliefs; (4) pain self-efficacy; (5) depression and anxiety; (6) disability will be measured. All outcomes will be measured at baseline, and again at 3-, 6-, and 12-months post allocation. DISCUSSION: The effective delivery of self-management strategies to prevent recurrence of low back pain is an important aspect that requires urgent attention. This study will provide new information on the effectiveness of using an MI-CBT approach to facilitate self-management through education and exercise to improve low back pain outcomes. Evidence emerging from this trial has the potential to inform clinical practice and healthcare management of non-specific low back pain. TRIAL REGISTRATION: Prospectively registered with Australian New Zealand Clinical Trials Registry: ACTRN12623000746639 (10/07/2023).

Safety and effectiveness of using Disposable Ultrasonic shears to coagulate 5-7 mm blood vessels: protocol for a prospective, multicenter, randomized, parallel controlled, non-inferiority clinical trial.

BACKGROUND: The ultrasonic scalpel is widely used during surgery. It is safe and effective to close the pulmonary artery branch vessels of 7 mm or below with an ultrasonic energy device as reported. However, there have been no multicenter randomized clinical trial to assess the safety and effectiveness of using ultrasonic scalpel to coagulate 5-7 mm blood vessels in thoracic surgery. METHODS: This is a prospective, multicenter, randomized, parallel controlled, non-inferiority clinical trial. A total of 144 eligible patients planning to undergo lung or esophageal surgery will be randomly allocated to the experimental group and the control group. The investigational product (Disposable Ultrasonic Shears manufactured by Reach Surgical, Inc.) and the control product (Harmonic Ace + 7, 5 mm Diameter Shears with Advanced Hemostasis) will be used in each group. The primary endpoint is the success rate of coagulating target blood vessels during surgery. Secondary endpoints include postoperative rebleeding, intraoperative bleeding volume, drainage volume, surgical duration, etc. Postoperative follow-up before and after discharge will be performed. DISCUSSION: This clinical trial aims to evaluate the safety and effectiveness of using the investigational product (Disposable Ultrasonic Shears manufactured by Reach Surgical, Inc.) and that of the control product (Harmonic Ace + 7, 5 mm Diameter Shears with Advanced Hemostasis) to coagulate 5-7 mm blood vessels in thoracic surgery. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06002737. The trial was prospectively registered on 16 August 2023, https://www. CLINICALTRIALS: gov/study/NCT06002737 .

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.