Switch to fixed-dose ainuovirine, lamivudine, and tenofovir DF versus elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV-1: the 48-week results of the SPRINT trial, a multi-centre, randomised, double-blind, active-controlled, phase 3, non-inferiority trial.

Background: We compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen. Methods: This study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150 mg plus lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (ANV/3TC/TDF), or cobicistat (Cobi) 150 mg boosted EVG plus emtricitabine (FTC) 200 mg, and tenofovir alafenamide (TAF) 10 mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605. Findings: Between October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n = 381) or EVG/Cobi/FTC/TAF (n = 381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI -1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05 kg, ETD -0.90 kg, 95% CI, -1.43 to -0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF. Interpretation: In virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF. Funding: Jiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.

Evaluating the Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) for Clinical Trials of Antibiotics in Pediatric Pneumonia.

Objective outcomes for pediatric community-acquired pneumonia (CAP) are lacking. The desirability of outcome ranking (DOOR) and response adjusted for duration of antibiotic risk (RADAR) outcome encompass clinical benefit and adverse effects, while also accounting for antibiotic exposure. We evaluated DOOR/RADAR through simulations and compared sample size considerations to non-inferiority designs in a hypothetical trial comparing antibiotics to no antibiotics (i.e., placebo) for children with mild CAP. We also evaluated a trial comparing different durations of antibiotics. Three scenarios were considered - one with no difference in DOOR between the two groups, one in which placebo is more efficacious, and another in which amoxicillin is more efficacious than placebo. Power to detect a difference between arms was greater using DOOR/RADAR compared to DOOR. Assuming a sample size of 200, DOOR had 2.5%, 50%, and 65% power to detect a statistical difference between arms for Scenarios 1-3, respectively, significantly less than DOOR/RADAR. Importantly, DOOR/RADAR incorrectly identified placebo as superior in Scenario 3 where amoxicillin was truly efficacious. Sample size requirements for non-inferiority designs were larger to achieve similar levels of power as DOOR and DOOR/RADAR. DOOR/RADAR has the potential to lead to an incorrect conclusion declaring placebo superior when amoxicillin is efficacious.

Stacked generalization as a computational method for the genomic selection.

As genomic selection emerges as a promising breeding method for both plants and animals, numerous methods have been introduced and applied to various real and simulated data sets. Research suggests that no single method is universally better than others; rather, performance is highly dependent on the characteristics of the data and the nature of the prediction task. This implies that each method has its strengths and weaknesses. In this study, we exploit this notion and propose a different approach. Rather than comparing multiple methods to determine the best one for a particular study, we advocate combining multiple methods to achieve better performance than each method in isolation. In pursuit of this goal, we introduce and develop a computational method of the stacked generalization within ensemble methods. In this method, the meta-model merges predictions from multiple base models to achieve improved performance. We applied this method to plant and animal data and compared its performance with currently available methods using standard performance metrics. We found that the proposed method yielded a lower or comparable mean squared error in predicting phenotypes compared to the current methods. In addition, the proposed method showed greater resistance to overfitting compared to the current methods. Further analysis included statistical hypothesis testing, which showed that the proposed method outperformed or matched the current methods. In summary, the proposed stacked generalization integrates currently available methods to achieve stable and better performance. In this context, our study provides general recommendations for effective practices in genomic selection.

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.

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.

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.

Comparison of a Supervised Home-Based Tele-Rehabilitation with Center-Based Pulmonary Rehabilitation: Protocol for a Randomized Non-Inferiority Multicenter Study in Ningxia.

Background: Pulmonary rehabilitation (PR) is an effective intervention for people with chronic obstructive pulmonary disease (COPD). However, fewer than 5% of eligible individuals receive pulmonary rehabilitation, largely due to limited by the accessibility of rehabilitation and difficulties associated with travel and transport. Supervised home-based tele-rehabilitation (SHTR) is an alternative model to center-based pulmonary rehabilitation. We will determine whether supervised home-based tele-rehabilitation is non-inferior to center-based pulmonary rehabilitation. Methods: The participants will undergo an 8-week rehabilitation program. Pulmonary rehabilitation comprises four main modules: exercise training, education, nutritional support, and psychological and behavioral interventions. We mainly focus on the module of exercise training and education. The education module includes information on exercise training, nutrition, and psychology, which are presented in an educational booklet provided to each participant. Blinded assessors will evaluate the outcomes at baseline, post-intervention, and 6 months after the intervention. The primary outcome is the change in the 6-minute walking distance. Secondary outcomes will assess changes in the patients' 1-minute sit-to-stand test, maximal inspiratory pressure (MIP), scales (CAT, mMRC, HAD), diaphragm ultrasound (TD, DE, DIF), changes in extrathoracic muscle volume and mass, completion rate of patient exercise prescriptions, occurrence of adverse events, as well as disease exacerbation and rehospitalization rates after rehabilitation and during the 6-month follow-up. Discussion: In order to improve the accessibility of pulmonary rehabilitation and patient-related outcomes, it is necessary to propose an alternative model of pulmonary rehabilitation. This trial will establish whether a supervised home-based tele-rehabilitation is not inferior to traditional center-based pulmonary rehabilitation. Trial Registration: Chinese Clinical Trial Registry ChiCTR2300076969. Registered on October 25, 2023.

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®.

A phase 3 non-inferiority trial of locally manufactured Meningococcal ACWY vaccine 'Ingovax ACWY' among Bangladeshi adults.

Meningococcal disease is caused by Neisseria meningitidis or meningococcus. Every year globally around 1.2 million people are affected and approximately 120,000 deaths occur due to meningitis. The disease can be prevented by a single dose of meningococcal vaccine. We carried out a randomized observer-blinded non-inferiority trial to evaluate and compare the immunogenicity and safety of a local meningococcal polysaccharide vaccine 'Ingovax ACWY' (test) with Quadri MeningoTM (comparator), an approved meningococcal polysaccharide vaccine in India. A total of 88 healthy adults (18-45 years old) were randomized at a 1:1 ratio in two vaccine groups receiving a single dose vaccine subcutaneously. All participants were followed until three months post-vaccination. Blood for clinical parameters (hematology and biochemistry) and serum bactericidal assay (SBA) was collected prior to vaccination and one-month post-vaccination. Solicited adverse events (AEs) were assessed up to 6 days following vaccination and unsolicited AEs were monitored throughout the follow-up period. There was no significant difference in rates of AE between the two groups. The commonest solicited AE was injection site pain. No serious AEs were reported. There was no significant difference (p<0.05) in seroconversion rate as well as pre and post-vaccination SBA geometric mean titers (GMT)between test and comparator vaccine. The post-vaccination GMT ratio (GMR) of the test and comparator vaccine was found to be 0.9, 1, 1.29, and 0.85 for serogroup A, C, W135, and Y respectively. For all the serogroups, lower limit of 95% CI of the GMR was found to be greater than the pre-defined 0.5 non-inferiority margin suggesting that Ingovax ACWY is similar to Quadri MeningoTM vaccine. We observed the immunogenicity and safety of Ingovax ACWY is non-inferior to comparator vaccine. The development of facilities for manufacturing polysaccharide ACWY vaccines locally will further lead to capacity building in the field of vaccines for Bangladesh.

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.

Investigating non-inferiority of internet-delivered versus face-to-face cognitive behavioural therapy for insomnia (CBT-I): a randomised controlled trial (iSleep well).

BACKGROUND: Insomnia is a highly prevalent disorder associated with numerous adverse health outcomes. Cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment by clinical guidelines but is accessible to only a minority of patients suffering from insomnia. Internet-delivered CBT-I (iCBT-I) could contribute to the widespread dissemination of this first-line treatment. As there is insufficient evidence regarding non-inferiority, this study directly aims to compare therapist-guided internet-delivered versus face-to-face CBT-I in terms of insomnia severity post-treatment. Furthermore, a health-economic evaluation will be conducted, and potential benefits and disadvantages of therapist-guided iCBT-I will be examined. METHODS: This study protocol describes a randomised controlled two-arm parallel-group non-inferiority trial comparing therapist-guided iCBT-I with face-to-face CBT-I in routine clinical care. A total of 422 patients with insomnia disorder will be randomised and treated at 16 study centres throughout Germany. Outcomes will be assessed at baseline, 10 weeks after randomisation (post), and 6 months after randomisation (follow-up). The primary outcome is insomnia severity measured using the Insomnia Severity Index. Secondary outcomes include depression-related symptoms, quality of life, fatigue, physical activity, daylight exposure, adverse events related to treatment, and a health-economic evaluation. Finally, potential moderator variables and several descriptive and exploratory outcomes will be assessed (e.g. benefits and disadvantages of internet-delivered treatment). DISCUSSION: The widespread implementation of CBT-I is a significant healthcare challenge. The non-inferiority of therapist-guided iCBT-I versus face-to-face CBT-I will be investigated in an adequately powered sample in routine clinical care, with the same therapeutic content and same level of therapist qualifications provided with both interventions. If this trial demonstrates the non-inferiority of therapist-guided iCBT-I, healthcare providers may be more confident recommending this treatment to their patients, contributing to the wider dissemination of CBT-I. TRIAL REGISTRATION: Trial registration number in the German Clinical Trials Register: DRKS00028153 ( https://drks.de/search/de/trial/DRKS00028153 ). Registered on 16th May 2023.

The Impacts of Task Shifting on the Management and Treatment of Malnourished Children in Northern Kenya: A Cluster-Randomized Controlled Trial.

Treating children with acute malnutrition can be challenging, particularly regarding access to healthcare facilities during treatment. Task shifting, a strategy of transferring specific tasks to health workers with shorter training and fewer qualifications, is being considered as an effective approach to enhancing health outcomes in primary healthcare. This study aimed to assess the effectiveness of integrating the treatment of acute malnutrition by community health volunteers into integrated community case management in two sub-counties in northern Kenya (Loima and Isiolo). We conducted a two-arm non-inferiority cluster-randomized controlled trial across 20 community health units. Participants were children aged 6-59 months with uncomplicated acute malnutrition. In the intervention group, community health volunteers used simplified tools and protocols to identify and treat eligible children at home and provided the usual integrated community case management package. In the control group, community health volunteers provided the usual integrated community case management package only (screening and referral of the malnourished children to the health facilities). The primary outcome was recovery (MUAC ≥12.5 cm for two consecutive weeks). Results show that children in the intervention group were more likely to recover than those in the control group [73 vs. 50; risk difference (RD)=26% (95% CI 12 to 40) and risk ratio (RR)=2 (95% CI 1.2 to 1.9)]. The probability of defaulting was lower in the intervention group than in the control group: RD=-21% (95% CI -31 to -10) and RR=0.3 (95% CI 0.2 to 0.5). The intervention reduced the length of stay by about 13 days, although this was not statistically significant and varied substantially by sub-county. Integrating the treatment of acute malnutrition by community health volunteers into the integrated community case management program led to better malnutrition treatment outcomes. There is a need to integrate acute malnutrition treatment into integrated community case management and review policies to allow community health volunteers to treat uncomplicated acute malnutrition.

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.

Metacognitive therapy versus exposure and response prevention for obsessive-compulsive disorder - A non-inferiority randomized controlled trial.

OBJECTIVE: Exposure with response prevention (ERP) is the first-line treatment for obsessive-compulsive disorder (OCD). However, refusals, dropouts and the required high time and logistic effort constitute barriers to the use of ERP. In a non-inferiority randomized controlled trial, we compared metacognitive therapy (MCT) to exposure with response prevention (ERP) as treatments for OCD. METHOD: 74 outpatients received 12 weekly sessions of either manualized MCT or ERP, with primary outcomes assessed by blinded assessors using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at pre-treatment, mid-treatment, post-treatment, and 6-month follow-up. Secondary outcomes included measures of depression and anxiety. Non-inferiority margin was specified at no less than d = 0.38 below the improvement reached by ERP, corresponding to a difference of about 3 points on the Y-BOCS. RESULTS: Drop-out rates were low (<14%) and similar in both groups. Linear models indicated non-inferiority of MCT to ERP at post-treatment, but not at 6-month follow-up. While both groups showed comparable Y-BOCS improvements, the MCT group demonstrated a significantly greater reduction in state anxiety scores at post-treatment and follow-up. CONCLUSIONS: Overall, MCT was not inferior to ERP, especially at post-treatment, suggesting it could be a treatment alternative. However, further research is needed to explore differential treatment indications.

Veterans' 12-month PTSD and depression outcomes following 2- and 3-week intensive cognitive processing therapy-based treatment.

Background: Growing evidence indicates that daily delivery of evidence-based PTSD treatments (e.g. Cognitive Processing Therapy (CPT)), as part of intensive PTSD treatment programmes (ITPs), is feasible and effective. Research has demonstrated that a 2-week CPT-based ITP can produce equivalent outcomes to a 3-week ITP, suggesting shorter treatment can also be highly effective. However, the extent to which ITP length and composition impact longer-term outcomes needs further study.Objective: We examined whether PTSD and depression symptoms 3-, 6-, and 12-months following completion of a 2-week ITP could be considered non-inferior, or equivalent, to those of a 3-week ITP.Method: Data from 638 veterans who participated in a 2-week CPT-based ITP were evaluated against 496 veterans who participated in a 3-week CPT-based ITP. A Bayes factor approach was used to examine whether PTSD and depression severity outcomes of the 2-week ITP could be considered equivalent to the 3-week ITP.Results: Participants across both ITPs reported large PTSD (d = 0.98) and moderate to large depression symptom reductions (d = 0.69) from baseline to 12-month follow-up. The PTSD and depression symptom reductions seen in the 2-week ITP were determined to be equivalent to those of the 3-week ITP.Conclusions: Low follow-up completion was a limitation. Future research might replicate the present findings using samples with greater follow-up rates and explore whether adjunctive services impact other relevant constructs, such as quality of life and functioning.

This study demonstrated that intensive PTSD treatment programmes for veterans can produce large and lasting PTSD and depression symptoms reductions.A 2-week intensive PTSD treatment programme that offered 37 fewer clinical hours was just as effective as a 3-week programme for veterans, with lasting symptom improvement up to 12 months after treatment.The 2-week programme focused primarily on individual Cognitive Processing Therapy delivered twice per day whereas the 3-week programme combined individual and group CPT and had a much larger number of adjunctive services.

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.

Disparate kinetics in immune response of two different Haemophilus influenzae type b conjugate vaccines: Immunogenicity and safety observations from a randomized controlled phase IV study in healthy infants and toddlers using a 2+1 schedule.

Since the introduction of Haemophilus Influenzae type b (Hib) conjugate vaccines, invasive Hib disease has strongly declined worldwide, yet continued control of Hib disease remains important. In Europe, currently three different hexavalent combination vaccines containing Hib conjugates are marketed. In this phase IV, single-blind, randomized, controlled, multi-country study (NCT04535037), we aimed to compare, in a 2 + 1 vaccination schedule, the immunogenicity and safety and show non-inferiority, as well as superiority, of DTPa-HBV-IPV/Hib (Ih group) versus DTaP5-HB-IPV-Hib (Va group) in terms of anti-polyribosylribitol phosphate (PRP) antibody geometric mean concentrations (GMCs) and proportion of participants reaching anti-PRP antibody concentrations greater than or equal to a threshold of 5 µg/mL. One month after the booster vaccination, the anti-PRP antibody GMC ratio (Ih group/Va group) was 0.917 (95% CI: 0.710-1.185), meeting the non-inferiority criteria. The difference in percentage of participants (Ih group - Va group) reaching GMCs ≥5 µg/mL was -6.3% (95% CI: -14.1% to 1.5%), not reaching the predefined non-inferiority threshold. Interestingly, a slightly higher post-booster antibody avidity was observed in the Ih group versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. This study illustrates the different kinetics of the anti-PRP antibody response post-primary and post-booster using the two vaccines containing different Hib conjugates and indicates a potential differential impact of concomitant vaccinations on the anti-PRP responses. The clinical implications of these differences should be further studied.

Vaccination against Haemophilus influenzae type b (Hib) is included in the majority of national immunization programs worldwide and has shown to be effective in preventing Hib disease. In Europe, different vaccines containing Hib components are marketed. We compared the immune response and safety of 2 of these (DTPa-HBV-IPV/Hib, Ih group) and DTaP5-HB-IPV-Hib, Va group) in infants and toddlers, when used in a 2 + 1 schedule, i.e. two primary vaccination doses (at 2 and 4 months of age of the infant), followed by one booster dose at the age of one year. One month after the booster vaccination, the antibody concentration ratio between both groups (Ih group/Va group) was 0.917 (95% CI: 0.710­1.185) showing the DTPa-HBV-IPV/Hib vaccine was non-inferior to the DTaP5-HB-IPV-Hib vaccine; the difference in percentage of participants (Ih group ­ Va group) with antibody concentrations above 5 µg/mL was -6.3% (95% CI: −14.1% to 1.5%), which did not meet the pre-defined criterion for non-inferiority. In the Ih group, the quality of antibodies produced was somewhat higher versus the Va group. Both vaccines were well tolerated, and no safety concerns were raised. The kinetics of the immune response are different between the 2 vaccines. Since both vaccines contain different additional components (conjugated proteins), a possible effect of concomitant (simultaneously administered) vaccines was studied. Further investigations to confirm our findings are needed.

Real-World Comparative Effectiveness Assessment Study of a Native Type I Collagen Matrix Plus Polyhexamethylene Biguanide Antimicrobial and a Cryopreserved Cadaveric Skin Allograft for Use in Diabetic Foot Ulcers - A Non-inferiority Analysis.

Objective: To determine the effectiveness of a native type I collagen matrix plus polyhexamethylene biguanide antimicrobial (PCMP) and a cryopreserved cadaveric skin allograft (CCSA) for use in diabetic foot ulcers (DFUs). Methods: A real-world data study was conducted on 989 DFUs analyzed digitally. Of these, 325 and 664 DFUs were treated with PCMP and CCSA, respectively. Non-inferiority testing for equivalence of PCMP and CCSA was performed at a level of significance of P < .05. Results: Cox proportional hazards regression analysis for healing for PCMP and CCSA at weeks 4, 8, 12, and 24 was 12% vs 10%, 27% vs 24%, 39 % vs 37%, and 60% vs. 64%, respectively. No statistically significant differences were shown; P = .95. The median time to healing was 18 and 17 weeks for PCMP and CCSA, respectively; P = .95. The probability of healing was statistically equivalent between PCMP and CCSA; hazard ratio = 0.99; 95% CI (0.85, 1.17). Non-inferiority statistical testing results showed P = .01. Conclusions: Using non-inferiority hypothesis testing at a level of significance of P <.05, we showed that PCMP was equivalent to CCSA; P = .01. PCMP vs CCSA demonstrated no statistically significant differences in median time, percentage, and probability of healing. Data from real-world data comparative effectiveness assessment studies can help guide clinicians to limit overuse of ineffective therapies and underuse of effective therapies.

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.