Temporary treatment cessation compared with continuation of tyrosine kinase inhibitors for adults with renal cancer: the STAR non-inferiority RCT.

Background: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration: This trial is registered as ISRCTN06473203. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients' disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient's quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible.

Non-inferiority, randomised, open-label clinical trial on the effectiveness of transurethral microwave thermotherapy compared to prostatic artery embolisation in reducing severe lower urinary tract symptoms in men with benign prostatic hyperplasia: study protocol for the TUMT-PAE-1 trial.

BACKGROUND: One-fourth of men older than 70 years have lower urinary tract symptoms (LUTS) that impair their quality of life. Transurethral resection of the prostate (TURP) is considered the gold standard for surgical treatment of LUTS caused by benign prostatic hyperplasia (BPH) that cannot be managed conservatively or pharmacologically. However, TURP is only an option for patients fit for surgery and can result in complications. Transurethral microwave thermotherapy (TUMT) and prostatic artery embolisation (PAE) are alternative minimally invasive surgical therapies (MISTs) performed in an outpatient setting. Both treatments have shown to reduce LUTS with a similar post-procedure outcome in mean International Prostate Symptom Score (IPSS). It is however still unknown if TUMT and PAE perform equally well as they have never been directly compared in a randomised clinical trial. The objective of this clinical trial is to assess if PAE is non-inferior to TUMT in reducing LUTS secondary to BPH. METHODS: This study is designed as a multicentre, non-inferiority, open-label randomised clinical trial. Patients will be randomised with a 1:1 allocation ratio between treatments. The primary outcome is the IPSS of the two arms after 6 months. The primary outcome will be evaluated using a 95% confidence interval against the predefined non-inferiority margin of + 3 points in IPSS. Secondary objectives include the comparison of patient-reported and functional outcomes at short- and long-term follow-up. We will follow the patients for 5 years to track long-term effect. Assuming a difference in mean IPSS after treatment of 1 point with an SD of 5 and a non-inferiority margin set at the threshold for a clinically non-meaningful difference of + 3 points, the calculated sample size was 100 patients per arm. To compensate for 10% dropout, the study will include 223 patients. DISCUSSION: In this first randomised clinical trial to compare two MISTs, we expect non-inferiority of PAE to TUMT. The most prominent problems with MIST BPH treatments are the unknown long-term effect and the lack of proper selection of candidates for a specific procedure. With analysis of the secondary outcomes, we aspire to contribute to a better understanding of durability and provide knowledge to guide treatment decisions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05686525. Registered on January 17, 2023, https://clinicaltrials.gov/study/NCT05686525 .

Real-world overall survival after alternative dosing for pembrolizumab in the treatment of non-small cell lung cancer: A nationwide retrospective cohort study with a non-inferiority primary objective.

BACKGROUND: High and increasing expenses on pembrolizumab ask for more cost-effective and sustainable treatment strategies to improve affordability of healthcare. Therefore, a part of the Dutch hospitals implemented an alternative, partially lower, weight-based dosing protocol for pembrolizumab. This provided the unique opportunity to compare the overall survival (OS) of the alternative pembrolizumab dosing protocol to standard dosing using a nationwide registry in non-small cell lung cancer (NSCLC) patients. METHODS: This is a retrospective cohort study with a non-inferiority primary objective. Forty hospitals in the Dutch Medication Audit and Dutch Lung Cancer Audit treated 1966 patients with NSCLC with first line pembrolizumab (mono- or combination therapy) between Jan 1st 2021, and Mar 31st, 2023. Alternative weight-based pembrolizumab dosing (100/150/200 mg Q3W or 200/300/400 mg Q6W) was administered to 604 patients, and 1362 patients received standard pembrolizumab dosing (200 mg Q3W or 400 mg Q6W). A Cox proportional hazard model with selected covariates was used to compare the OS between alternative and standard dosing protocols. The non-inferiority margin was set at a hazard ratio (HR) of 1.2 for OS. Non-inferiority is established by showing that the upper limit of the 95 % confidence interval (CI) of the HR of OS is smaller or equal to 1.2. RESULTS: Distribution of age (66.7 years +/-9.4), sex (45 % female) and treatment combinations were similar for both groups, comorbidity score was higher in the standard group. Median daily dose in the alternative dosing group was 22 % lower compared to the standard dosing group, 7.14 mg/day (interquartile range (IQR):5.48-8.04 mg/day) vs. 9.15 mg/day (IQR:8.33-9.52 mg/day), respectively. Alternative dosing was non-inferior to standard dosing regarding overall survival (adjusted HR 0.83, 95 %CI:0.69-1.003). CONCLUSION: This large, retrospective real-world analysis supports the hypothesis that the alternative, partially lower pembrolizumab dosing protocol in NSCLC maintains treatment effectiveness while reducing treatment costs.

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

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

Laparoscopy is non-inferior to open surgery for rectal cancer: A systematic review and meta-analysis.

BACKGROUND: Laparoscopic surgery has been endorsed by clinical guidelines for colon cancer, but not for rectal cancer on account of unapproved oncologic equivalence with open surgery. AIMS: We started this largest-to-date meta-analysis to comprehensively evaluate the safety and efficacy of laparoscopy in the treatment of rectal cancer compared with open surgery. MATERIALS & METHODS: Both randomized and nonrandomized controlled trials comparing laparoscopic proctectomy and open surgery between January 1990 and March 2020 were searched in PubMed, Cochrane Library and Embase Databases (PROSPERO registration number CRD42020211718). The data of intraoperative, pathological, postoperative and survival outcomes were compared between two groups. RESULTS: Twenty RCTs and 93 NRCTs including 216,615 patients fulfilled the inclusion criteria, with 48,888 patients received laparoscopic surgery and 167,727 patients underwent open surgery. Compared with open surgery, laparoscopic surgery group showed faster recovery, less complications and decreased mortality within 30 days. The positive rate of circumferential margin (RR = 0.79, 95% CI: 0.72 to 0.85, p < 0.0001) and distal margin (RR = 0.75, 95% CI: 0.66 to 0.85 p < 0.0001) was significantly reduced in the laparoscopic surgery group, but the completeness of total mesorectal excision showed no significant difference. The 3-year and 5-year local recurrence, disease-free survival and overall survival were all improved in the laparoscopic surgery group, while the distal recurrence did not differ significantly between the two approaches. CONCLUSION: Laparoscopy is non-inferior to open surgery for rectal cancer with respect to oncological outcomes and long-term survival. Moreover, laparoscopic surgery provides short-term advantages, including faster recovery and less complications.

Efficacy and safety of cytisine versus nortriptyline for smoking cessation: A multicentre, randomized, double-blinded and placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Cytisine serves as an affordable smoking cessation aid with acceptable safety profile. However, data comparing its efficacy and safety to standard therapies are limited. We aimed to examine efficacy and safety of cytisine compared to nortriptyline, which is the only approved smoking-cessation medication in Thailand. METHODS: A 12-month, multicentre, randomized, double-blinded, placebo-controlled trial was conducted. Participants aged ≥20 years who smoked ≥10 cigarettes/day were randomly assigned to receive a 25-day cytisine or a 12-week nortriptyline treatment course. Brief interventions (BI) for smoking cessation were provided to all participants. The primary outcome was biochemically verified continuous abstinence rate (CAR) at 12 months. Additionally, self-reported abstinence, verified by exhaled carbon monoxide (CO) ≤ 10 ppm, was collected at 2 weeks, 1, 3, 6 and 12 months to assess both CAR and 7-day point prevalence abstinence rate (PAR). RESULTS: A total of 1086 participants were recruited and randomized into cytisine (n = 540) and nortriptyline (n = 546) groups. The 12-month CAR was 12.22% for cytisine and 9.52% for nortriptyline. The relative difference was 0.03 (95% confidence interval [CI]; -0.01 to 0.06) and the relative risk was 1.28 (95% CI; 0.91-1.81). No differences were observed in secondary outcomes between both groups. The incidence of adverse effects from cytisine appeared to be lower than that of nortriptyline. CONCLUSION: At 12 months, cytisine plus BI was as effective as nortriptyline plus BI for smoking cessation. The adverse events for both cytisine and nortriptyline were minimal and well-tolerated.

Non-operative management of uncomplicated appendicitis in children: a randomized, controlled, non-inferiority study evaluating safety and efficacy.

BACKGROUND: Appendicitis is the commonest paediatric surgical emergency. Adult studies suggest non-operative management (NOM) may have a place in care. There have been no adequately powered randomized controlled trials in children. OBJECTIVE: to determine the safety and efficacy of NOM for paediatric simple appendicitis. METHODS: A non-inferiority randomized controlled trial was conducted comparing operative (OM) to NOM of SA in children aged five-15 years. Primary outcome was treatment success (no unplanned or unnecessary operation, or complication) at 30 days and 12 months, with a non-inferiority margin of 15%. (anzctr.org.au: ACTRN12616000788471). RESULTS: From 11 June 2016 to 30 November 2020, 222 children were randomized: 94 (42.34%) to OM and 128 (57.66%) to NOM. Non-inferiority of NOM was not demonstrated at either time point, with 45.67% of NOM patients subsequently undergoing operation. There was no significant difference in complications. CONCLUSIONS: While noninferiority was not shown, NOM was safe, with no difference in adverse outcomes between the two groups. Further research to refine the place of NOM of simple appendicitis in children is required, including nuanced patient selection, longer term evaluation, the place of choice, and the acceptability of the treatment for children and their carers.

Caffeic acid phenethyl ester derivative exerts remarkable anti-hepatocellular carcinoma effect, non-inferior to sorafenib, in vivo analysis.

Caffeic acid phenethyl ester (CAPE) and its derivatives exhibit considerable effects against hepatocellular carcinoma (HCC), with unquestioned safety. Here we investigated CAPE derivative 1' (CAPE 1') monotherapy to HCC, compared with sorafenib. HCC Bel-7402 cells were treated with CAPE 1', the IC50 was detected using CCK-8 analysis, and acute toxicity testing (5 g/kg) was performed to evaluate safety. In vivo, tumor growth after CAPE 1' treatment was evaluated using an subcutaneous tumor xenograft model. Five groups were examined, with group 1 given vehicle solution, groups 2, 3, and 4 given CAPE 1' (20, 50, and 100 mg/kg/day, respectively), and group 5 given sorafenib (30 mg/kg/day). Tumor volume growth and tumor volume-to-weight ratio were calculated and statistically analyzed. An estimated IC50 was 5.6 µM. Acute toxicity tests revealed no animal death or visible adverse effects with dosage up to 5 g/kg. Compared to negative controls, CAPE 1' treatment led to significantly slower increases of tumor volume and tumor volume-to-weight. CAPE 1' and sorafenib exerted similar inhibitory effects on HCC tumors. CAPE 1' was non-inferior to sorafenib for HCC treatment, both in vitro and in vivo. It has great potential as a promising drug for HCC, based on effectiveness and safety profile.

Superparamagnetic iron oxide (SPIO) for sentinel lymph node detection in vulvar cancer.

OBJECTIVES: Sentinel lymph node (SLN) detection with superparamagnetic iron oxide (SPIO) nanoparticles has been widely studied and standardized for breast and prostate cancer, but there is scarce evidence concerning its use in vulvar cancer. The objective of this study was to compare SLN detection using a SPIO tracer injected at the time of the surgery detected by a magnetometer, with the standard procedure of using a technetium 99 radioisotope (Tc99) detected by a gamma probe, in patients with vulvar cancer. METHODS: The SPIO vulvar cancer study was a single-center prospective interventional non-inferiority study of SPIO compared to Tc99, conducted between 2016 and 2021 in patients who met the GROINSS-V study inclusion criteria for selective sentinel lymph node dissection in vulvar cancer. RESULTS: We included 18 patients and a total of 41 SLNs. The level of agreement between tracers was 92.7% (80.6%-97.4%), corresponding to 38 out of 41 SLNs, which confirms the non-inferiority of SPIO compared to Tc99. The SLN detection rate per groin was 96.3 (81.7%-99.3) using Tc99 and 100% (87.5%-100%) using SPIO. Both tracers had a detection rate of 100% for positive lymph nodes. CONCLUSIONS: The use of SPIO as a tracer for detecting SLNs in patients with vulvar cancer has shown to be non-inferior to that of the standard radiotracer, with the advantages of not requiring nuclear medicine and being able to inject it at the time of surgery after induction of anesthesia.

Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease.

Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA, leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2 years showed that the intergroup difference [95%confidence interval] in the median slope was -0.36 mL/min/1.73 m2/year [-2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of -3 mL/min/1.73 m2/year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective.

Evaluation of the analgesic efficacy of grapiprant compared with robenacoxib in cats undergoing elective ovariohysterectomy in a prospective, randomized, masked, non-inferiority clinical trial.

OBJECTIVES: The main objective of this study was to compare the postoperative analgesic effects of grapiprant with those of robenacoxib in cats undergoing ovariohysterectomy (OVH). METHODS: In total, 37 female cats (age range 4 months-10 years, weighing ⩾2.5 kg) were enrolled in a prospective, randomized, masked, non-inferiority (NI) clinical trial. Cats received oral robenacoxib (1 mg/kg) or grapiprant (2 mg/kg) 2 h before OVH. Analgesia was assessed via the Feline Grimace Scale (FGS), the Glasgow Composite Measure Pain Scale-Feline (CMPS-F), von Frey monofilaments (vFFs) and pressure algometry (ALG) 2 h before treatment administration, at extubation, and 2, 4, 6, 8, 18 and 24 hours after extubation. Hydromorphone (<8 h postoperatively) or buprenorphine (>18 h postoperatively) were administered to cats with scores of ⩾5/20 on CMPS-F and/or ⩾4/10 on FGS. NI margins for CMPS-F and vFFs were set at 3 and -0.2, respectively. A mixed-effect ANOVA was used for FGS scores (P <0.05). Data are reported as mean ± SEM. RESULTS: The data from 33 cats were analyzed. The upper limit of the 95% confidence interval (CI) (0.35) was less than the NI margin of 3 for CMPS-F, and the lower limit of the 95% CI (0.055) was greater than the NI margin of -0.2 for vFFs, indicating NI of grapiprant. The FGS scores were greater than baseline at extubation for both treatments (1.65 ± 0.63; P = 0.001); however, there was no difference between treatments. There was no difference between treatments, nor treatment by time interaction, for vFFs (P <0.001). The CMPS-F scores for both treatments were higher at extubation but returned to baseline after 4 h (P <0.001). For ALG, there was no difference in treatment or treatment by time interaction. The robenacoxib group had lower pressure readings at extubation and 6 h compared with baseline. CONCLUSIONS AND RELEVANCE: These results indicate that grapiprant was non-inferior to robenacoxib for mitigating postsurgical pain in cats after OVH performed via ventral celiotomy. The impact of grapiprant for analgesia in OVH via the flank is unknown.

A framework for testing non-inferiority in a three-arm, sequential, multiple assignment randomized trial.

Sequential multiple assignment randomized trial design is becoming increasingly used in the field of precision medicine. This design allows comparisons of sequences of adaptive interventions tailored to the individual patient. Superiority testing is usually the initial goal in order to determine which embedded adaptive intervention yields the best primary outcome on average. When direct superiority is not evident, yet an adaptive intervention poses other benefits, then non-inferiority testing is warranted. Non-inferiority testing in the sequential multiple assignment randomized trial setup is rather new and involves the specification of non-inferiority margin and other important assumptions that are often unverifiable internally. These challenges are not specific to sequential multiple assignment randomized trial and apply to two-arm non-inferiority trials that do not include a standard-of-care (or placebo) arm. To address some of these challenges, three-arm non-inferiority trials that include the standard-of-care arm are proposed. However, methods developed so far for three-arm non-inferiority trials are not sequential multiple assignment randomized trial-specific. This is because apart from embedded adaptive interventions, sequential multiple assignment randomized trial typically does not include a third standard-of-care arm. In this article, we consider a three-arm sequential multiple assignment randomized trial from an National Institutes of Health-funded study of symptom management strategies among people undergoing cancer treatment. Motivated by that example, we propose a novel data analytic method for non-inferiority testing in the framework of three-arm sequential multiple assignment randomized trial for the first time. Sample size and power considerations are discussed through extensive simulation studies to elucidate our method.

¿Ensayos clínicos de superioridad, equivalencia o no inferioridad? / ¿Clinical trials of superiority, non-inferiority or equivalence?

La eficacia de una nueva intervención se establece generalmente a través de ensayos clínicos (EC) con asignación aleatoria (AA). Sin embargo, entre otros tantos desafíos metodológicos, el especificar la hipótesis de un EC con AA, sigue siendo un problema complejo de resolver para los investigadores clínicos. En este manuscrito discutimos las características de tres variantes de los EC con AA: EC de superioridad (ECS), EC de no-inferioridad (ECNI), y EC de equivalencia (ECE). Estos tres tipos de EC tienen supuestos diferentes sobre los efectos de una intervención, por lo que plantear hipótesis y definir objetivos requiere conocer algunos supuestos subyacentes a estos EC, incluso hasta elementos relacionados con la estimación del tamaño de muestra para cada cual. El objetivo de este manuscrito fue describir las diferencias metodológicas entre ECS, ECNI y ECE.

Efficacy and effectivity of new interventions are generally established through randomized clinical trials (RCTs). However, among many other methodological challenges, specifying the hypothesis of a RCT remains complex problem for clinical researchers. In this manuscript we discuss the characteristics of three variants of RCTs: superiority RCT (SRCT), non-inferiority RCT (NIRCT), and equivalence RCT (ERCT). These three types of RCT have different assumptions about the effects of an intervention, so setting hypotheses and defining objectives requires knowing some assumptions underlying these RCTs, including elements related to the estimation of the sample size for each one. The aim of this manuscript was to describe methodological differences between SRCT, NIRCT and ERCT.

Telenutrition Education Is Effective for Glycemic Management in People with Type 2 Diabetes Mellitus: A Non-Inferiority Randomized Controlled Trial in Japan.

This study examined the non-inferior efficacy of telenutrition education compared with face-to-face nutrition education in managing glycemic control in people with type 2 diabetes mellitus (T2DM). Participants had T2DM and a glycated hemoglobin (HbA1c) ranged 6.5-9.5%. Thirty participants were randomly assigned to either the telenutrition or face-to-face nutrition education group. During the 32-week intervention period, the participants received four sessions on nutrition education from a registered dietitian at the hospital. The telenutrition group received remote education via a videoconferencing platform. Face-to-face nutrition education was conducted using paper-based instructions. The main outcome measure was the non-inferiority of HbA1c levels in the telenutrition group compared to the face-to-face nutrition group. The non-inferiority of telenutrition education was considered valid if the intergroup difference in the mean values of the change in HbA1c had a bilateral 95% confidence interval (CI) upper limit below 0.40%. The intergroup difference in the mean HbA1c change from baseline to the fourth nutrition education session was -0.11 (95% CI -0.54-0.32) for both groups. The upper limit of the bilateral 95% CI was 0.32%, which was below the 0.40% non-inferiority margin (non-inferiority test; p = 0.011). Telenutrition education was not inferior to face-to-face nutrition education for glycemic management in people with T2DM.

5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer.

BACKGROUND: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is the standard treatment for pathological stage II gastric cancer. The phase III trial (JCOG1104) investigating the non-inferiority of four courses of S-1 to eight courses was terminated due to futility at the first interim analysis. To confirm the primary results, we reported the results after a 5-years follow-up in JCOG1104. METHODS: Patients histologically diagnosed with stage II gastric cancer after radical gastrectomy were randomly assigned to receive S-1 for eight or four courses. In detail, 80 mg/m2/day S-1 was administered for 4 weeks followed by a 2-week rest as a single course. RESULTS: Between February 16, 2012, and March 19, 2017, 590 patients were enrolled and randomly assigned to 8-course (295 patients) and 4-course (295 patients) regimens. After a 5-years follow-up, the relapse-free survival at 3 years was 92.2% for the 8-course arm and 90.1% for the 4-course arm, and that at 5 years was 87.7% for the 8-course arm and 85.6% for the 4-course arm (hazard ratio 1.265, 95% CI 0.846-1.892). The overall survival at 3 years was 94.9% for the 8-course arm, 93.2% for the 4-course arm, and that at 5 years was 89.7% for the 8-course arm, and 88.6% for the 4-course arm (HR 1.121, 95% CI 0.719-1.749). CONCLUSIONS: The survival of the four-course arm was slightly but consistently inferior to that of the eight-course arm. Eight-course S-1 should thus remain the standard adjuvant chemotherapy for pathological stage II gastric cancer.

Design of a clinical trial using generalized pairwise comparisons to test a less intensive treatment regimen.

BACKGROUND/AIMS: Showing "similar efficacy" of a less intensive treatment typically requires a non-inferiority trial. Yet such trials may be challenging to design and conduct. In acute promyelocytic leukemia, great progress has been achieved with the introduction of targeted therapies, but toxicity remains a major clinical issue. There is a pressing need to show the favorable benefit/risk of less intensive treatment regimens. METHODS: We designed a clinical trial that uses generalized pairwise comparisons of five prioritized outcomes (alive and event-free at 2 years, grade 3/4 documented infections, differentiation syndrome, hepatotoxicity, and neuropathy) to confirm a favorable benefit/risk of a less intensive treatment regimen. We conducted simulations based on historical data and assumptions about the differences expected between the standard of care and the less intensive treatment regimen to calculate the sample size required to have high power to show a positive Net Treatment Benefit in favor of the less intensive treatment regimen. RESULTS: Across 10,000 simulations, average sample sizes of 260 to 300 patients are required for a trial using generalized pairwise comparisons to detect typical Net Treatment Benefits of 0.19 (interquartile range 0.14-0.23 for a sample size of 280). The Net Treatment Benefit is interpreted as a difference between the probability of doing better on the less intensive treatment regimen than on the standard of care, minus the probability of the opposite situation. A Net Treatment Benefit of 0.19 translates to a number needed to treat of about 5.3 patients (1/0.19 ≃ 5.3). CONCLUSION: Generalized pairwise comparisons allow for simultaneous assessment of efficacy and safety, with priority given to the former. The sample size required would be of the order of 300 patients, as compared with more than 700 patients for a non-inferiority trial using a margin of 4% against the less intensive treatment regimen for the absolute difference in event-free survival at 2 years, as considered here.

Intravenous tranexamic acid for intracerebral meningioma resections: A randomized, parallel-group, non-inferiority trial.

STUDY OBJECTIVES: Tranexamic acid (TXA) is an antifibrinolytic that is widely used to reduce surgical bleeding. However, TXA occasionally causes seizures and the risk might be especially great after neurosurgery. We therefore tested the hypothesis that TXA does not meaningfully increase the risk of postoperative seizures within 7 days after intracranial tumor resections. DESIGN: Randomized, double-blind, placebo-controlled, non-inferiority trial. SETTING: Beijing Tiantan Hospital, Capital Medical University. PATIENTS: 600 patients undergoing supratentorial meningioma resection were included from October 2020 to August 2022. INTERVENTIONS: Patients were randomly assigned to a single dose of 20 mg/kg of TXA after induction (n = 300) or to the same volume of normal saline (n = 300). MEASUREMENT: The primary outcome was postoperative seizures occurring within 7 days after surgery, analyzed in both the intention-to-treat and per-protocol populations. Non-inferiority was defined by an upper limit of the 95% confidence interval for the absolute difference being <5.5%. Secondary outcomes included incidence of non-epileptic complication within 7 days, changes in hemoglobin concentration, estimated intraoperative blood loss. Post hoc analyses included the types and timing of seizures, oozing assessment, and a sensitivity analysis for the primary outcome in patients with pathologic diagnosis of meningioma. MAIN RESULTS: All 600 enrolled patients adhered to the protocol and completed the follow-up for the primary outcome. Postoperative seizures occurred in 11 of 300 (3.7%) of patients randomized to normal saline and 13 of 300 (4.3%) patients assigned to tranexamic acid (mean risk difference, 0.7%; 1-sided 97.5% CI, -∞ to 4.3%; P = 0.001 for noninferiority). No significant differences were observed in any secondary outcome. Post hoc analysis indicated similar amounts of oozing, calculated blood loss, recurrent seizures, and timing of seizures. CONCLUSION: Among patients having supratentorial meningioma resection, a single intraoperative dose of TXA did not significantly reduce bleeding and was non-inferior with respect to postoperative seizures after surgery. REGISTRY INFORMATION: This trial was registered at clinicaltrials.gov (NCT04595786) on October 22, 2020, by Dr.Yuming Peng.

Efficacy and safety comparison of infrared laser moxibustion and traditional moxibustion in knee osteoarthritis: study protocol for a Zelen-design randomized controlled non-inferiority clinical trial.

BACKGROUND: Knee osteoarthritis (KOA) is the most common chronic degenerative joint disease and places a substantial burden on the public health resources in China. The purpose of this study is to preliminarily evaluate whether infrared laser moxibustion (ILM) is non-inferior to traditional moxibustion (TM) in the treatment of KOA. MATERIALS AND METHODS: In the designed Zelen-design randomized controlled non-inferiority clinical trial, a total of 74 patients with KOA will be randomly allocated to one of two interventions: ILM treatment or TM treatment. All participants will receive a 6-week treatment and a follow-up 4 weeks after treatment. The primary outcomes will be the mean change in pain scores on the numeric rating scale (NRS) measured at baseline and the end of last treatment at week 6. The secondary outcomes will be the pain scores on the NRS from weeks 1 to 5 after the start of treatment and the changes from baseline to endpoints (weeks 6 and 10) in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), SF-36, knee circumference, and 6-min walking test. In addition, safety assessment will be performed throughout the trial. CONCLUSION: The results of our study will help determine whether a 6-week treatment with ILM is non-inferior to TM in patients with KOA, therefore providing evidence to verify if ILM can become a safer alternative for TM in clinical applications in the future. TRIAL REGISTRATION: Clinical Trial Registration Platform (ChiCTR2200065264); Pre-results. Registered on 1 November 2022.