When designing a clinical trial to show whether a new or experimental therapy is as effective as a standard therapy (but not necessarily more effective), the usual null hypothesis of equality is inappropriate and leads to logical difficulties. Since therapies cannot be shown to be literally equivalent, the appropriate null hypothesis is that the standard therapy is more effective than the experimental therapy by at least some specified amount. The problem is presented in terms of a trial in which the outcome of interest is dichotomous; test statistics, confidence intervals, and sample size calculations are discussed. The required sample size may be larger for either null hypothesis formulation than for the other, depending on the specific assumptions made. Reporting results in terms of confidence intervals is especially useful for this type of trial.
2023, Journal of Plastic, Reconstructive and Aesthetic Surgery
Breast reconstruction (BR) surgery is a widely utilized approach for women who have undergone mastectomy. Using synthetic mesh can offer advantages over other materials providing long-lasting support and natural-looking results. This study aims to compare the effectiveness of 3DMax™ mesh to TIGR mesh in BR surgery, providing clear information about the non-inferiority of 3DMax™ mesh to TIGR.
This retrospective cohort study evaluates postoperative complications in breast cancer patients who underwent subcutaneous mastectomy with direct-to-implant immediate BR using silicone implants and either 3DMax™ mesh or TIGR® Matrix Surgical Mesh.
This study involved BR surgeries in 82 patients, including 57 surgeries in the 3D mesh group and 49 in the TIGR mesh group. The two groups had no significant differences regarding age, body mass index (BMI), cancer stage, or surgical complications. However, patients with neoadjuvant chemotherapy or radiotherapy had higher incidence rates of long-term complications than other patients. Patients with infection or partial necrosis had a heightened risk of implant loss.
The clinical results obtained in this study suggest that among synthetic meshes used in immediate BR, 3DMax™ is not inferior to TIGR Matrix Surgical Mesh regarding complications.
Smaller electrodes allow more options for design of automated external defibrillator (AED) user interfaces. However, previous studies employing monophasic-waveform defibrillators found that smaller electrode sizes have lower defibrillation shock success rates. We hypothesize that, for impedance-compensated, biphasic truncated exponential (BTE) shocks, smaller electrodes increase transthoracic impedance (TTI) but do not adversely affect defibrillation success rates.
In this prospective before-and-after clinical study, Amsterdam police and firefighters used AEDs with BTE waveforms: an AED with larger electrodes in 2016–2017 (113 cm2), and an AED with smaller electrodes in 2017–2020 (65 cm2). We analyzed 157 and 178 patient cases with an initial shockable rhythm where the larger and smaller electrodes were used, respectively. A single 200-J shock terminated ventricular fibrillation (VF) in 86% of patients treated with large electrodes and 89% of patients treated with smaller electrodes. Small electrodes had a non-inferior first shock defibrillation success rate compared to large electrodes, with a difference of 3% (95% CI: –3% −9%) with the lower confidence limit remaining above the defined non-inferiority threshold. TTI was significantly higher for the smaller electrodes (median: 100 Ω) compared to the larger electrodes (median: 88 Ω) (p < 0.001).
For AEDs with impedance-compensating BTE waveforms, TTI was higher for smaller electrodes than the large electrode electrodes. Overall defibrillation shock success for AEDs with smaller electrodes was non-inferior to the AEDs with larger electrodes.
The safety of tenofovir disoproxil fumarate and emtricitabine as pre-exposure prophylaxis (PrEP) in pregnant women not living with HIV is uncertain. We aimed to compare pregnancy and neonatal outcomes in women exposed and not exposed to PrEP during pregnancy.
In this single-site, open-label, randomised, non-inferiority trial in Durban, South Africa, we evaluated pregnancy and neonatal outcomes in pregnant women aged 18 years or older, not living with HIV, and at 14–28 weeks' gestation at the time of enrolment. Eligible participants were randomly assigned (1:1) using a computer-generated permuted block (block size of ten) randomisation list to immediate initiation or deferred initiation of PrEP until breastfeeding cessation. Participants in the immediate PrEP group received a monthly supply of once daily oral tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg. Participants in the deferred PrEP group received standard of care for HIV prevention. The primary outcomes were the occurrence of preterm live birth (<37 weeks gestational age) and very preterm birth (<34 weeks gestational age) determined by menstrual dating, low birthweight (<2500 g), very low birthweight (<1500 g), stillbirth (≥20 weeks gestational age), and small for gestational age (birthweight less than the tenth percentile). Post-natal safety outcomes will be reported elsewhere. We used binomial regression models to estimate risk differences and two-sided 90% CIs. Immediate PrEP was non-inferior to deferred PrEP if the upper bound of the 90% CI of the risk difference was less than the upper predefined non-inferiority margin for preterm birth (7·5%), very preterm birth (2·6%), low birthweight (5·5%), very low birthweight (1·2%), stillbirth (1·0%), and small for gestational age (3·7%). All outcomes were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT3227731.
Between Sept 25, 2017, and Dec 6, 2019, we screened 693 women, of whom 540 were randomly assigned to immediate PrEP (n=271) or deferred PrEP (n=269). The median gestational age was 19 weeks (IQR 15–23 for immediate PrEP and 16–23 for deferred PrEP). The risk difference between the immediate PrEP group and the deferred PrEP group for preterm birth was –4·7% (90% CI –10·7 to 1·2; immediate PrEP was non-inferior), for very preterm birth was 0·6% (–3·4 to 4·6; upper limit exceeded the non-inferiority margin), for low birthweight was 2·5% (–1·6 to 6·6; upper limit exceeded the non-inferiority margin), for very low birthweight was 0% (–1·4 to 1·4; upper limit exceeded the non-inferiority margin), for stillbirth was 1·2% (–1·5 to 3·8; upper limit exceeded the non-inferiority margin), and for small for gestational age was 0·9% (–1·2 to 2·9; immediate PrEP was non-inferior).
In our study, PrEP was not associated with preterm birth or small for gestational age infants. Our data support the use of tenofovir disoproxil fumarate and emtricitabine in pregnancy and our reassuring findings can be used to allay safety concerns among pregnant women.
South African Medical Research Council and Gilead Sciences.
The need for a comparison group in clinical trials is universally required. In the evaluation of drugs and biologics, experimental treatments are usually evaluated in a placebo-controlled trial, typically through a randomized controlled trial Due to significant innovation and proven-successful treatments across most fields, including a placebo group is unethical in most circumstances. To withhold efficacious treatments in the setting of a clinical trial would be harmful and unfair to the recipient. Thus, the implementation of noninferiority trials is conducted to compare a new experimental treatment with the standard of care. If the efficacy of a new treatment falls within the predetermined noninferiority margin, the experimental treatment is proven not inferior.
The chapter introduces Equivalence and Noninferiority trials. It starts by defining both types of trials and situations in which they may be used as opposed to randomized control trials, including the potential benefits. It then details the primary challenges associated with such trials, establishing a reasonable boundary margin and the crucial requirement for high-quality trials. The chapter ends with a step-by-step approach to conduct a noninferiority trial using a fabricated example comparing a novel biodegradable Inferior Vena Cana (IVC) filter to a standard control IVC filter. Additionally, there is a brief discussion about the modifications required to conduct an equivalence trial alternatively.
Thirty years ago, neurotoxicity induced by general anaesthetics in the developing brain of rodents was observed. In both laboratory-based and clinical studies, many conflicting results have been published over the years, with initial data confirming both histopathological and neurodevelopmental deleterious effects after exposure to general anaesthetics. In more recent years, animal studies using non-human primates and new human cohorts have identified some specific deleterious effects on neurocognition. A clearer pattern of neurotoxicity seems connected to exposure to repeated general anaesthesia. The biochemistry involved in this neurotoxicity has been explored, showing differential effects of anaesthetic drugs between the developing and developed brains. In this narrative review, we start with a comprehensive description of the initial concerning results that led to recommend that any non-essential surgery should be postponed after the age of 3 yr and that research into this subject should be stepped up. We then focus on the neurophysiology of the developing brain under general anaesthesia, explore the biochemistry of the observed neurotoxicity, before summarising the main scientific and clinical reports investigating this issue. We finally discuss the GAS trial, the importance of its results, and some potential limitations that should not undermine their clinical relevance. We finally suggest some key points that could be shared with parents, and a potential research path to investigate the biochemical effects of general anaesthesia, opening up perspectives to understand the neurocognitive effects of repetitive exposures, especially in at-risk children.