How do multi-stage, multi-arm trials compare to the traditional two-arm parallel group design – a reanalysis of 4 trials

<p>Abstract</p> <p>Background</p> <p>To speed up the evaluation of new therapies, the multi-arm, multi-stage trial design was suggested previously by the authors.</p> <p>Methods</p> <p>In this paper, we evaluate the performance of the two-stage, multi-arm design using four cancer trials conducted at the MRC CTU. The performance of the design at fictitious interim analyses is assessed using a conditional bootstrap approach.</p> <p>Results</p> <p>Two main aims are addressed: the error rate of correctly carrying on/stopping the trial at an interim analysis as well as quantifying the gains in terms of resources by employing this design. Furthermore, we make suggestions for the best timing of this interim analysis.</p> <p>Conclusion</p> <p>Multi-arm, multi-stage trials are an effective way of speeding up the therapy evaluation process. The design performs well in terms of the type I and II error rates.</p

Reporting of health estimates prior to GATHER: a scoping review

Background: Generating estimates of health indicators at the global, regional, and country levels is increasingly in demand in order to meet reporting requirements for global and country targets, such as the sustainable development goals (SDGs). However, such estimates are sensitive to availability of input data, underlying analytic assumptions, variability in statistical techniques, and often have important limitations. From a user perspective, there is often a lack of transparency and replicability. In order to define best practices in reporting data and methods used to calculate health estimates, the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) working group developed a minimum checklist of 18 items that must be reported within each study publishing health estimates, so that users may make an assessment of the quality of the estimate. Objective: We conducted a scoping review to assess the state of reporting amongst a cross-sectional sample of studies published prior to the publication of GATHER. Methods: We generated a sample of UN reports and journal articles through a combination of a Medline search and hand-searching published health estimates. From these studies we extracted the percentage of studies correctly reporting each item on the checklist, the proportion of items reported per study (the GATHER performance score), and how this score varied depending on study type. Results: The average proportion of items reported per study was 0.47, and the poorest-performing items related to documentation and availability of input data, availability of the statistical code used and the subsequent output data, and a complete detailed description of all the steps of the data analysis. Conclusions: Methods for health estimates are not currently fully reported, and the implementation of the GATHER guidelines will improve the availability of information required to make an assessment of study quality

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

In a phase II study, 43 renal cell carcinoma patients were treated with individualised doses of ABR-214936; a fusion of a Fab recognising the antigen 5T4, and Staphylococcal enterotoxin A. Drug was given intravenously on 4 consecutive days, treatment was repeated 1 month later. Treatment was associated with moderate fever and nausea, but well tolerated. Of 40 evaluable patients, 28 had disease control at 2 months, and at 4 months, one patient showed partial response (PR) and 16 patients stable disease. Median survival, with minimum follow-up of 26 months was 19.7 months with 13 patients alive to date. Stratification by the Motzer's prognostic criteria highlights prolonged survival compared to published expectation. Patients receiving higher drug exposure had greater disease control and lived almost twice as long as expected, whereas the low-exposure patients survived as expected. Sustained interleukin-2 (IL-2) production after a repeated injection appears to be a biomarker for clinical effect, as the induced-IL-2 level on the day 2 of treatment correlated with survival. The high degree of disease control and the prolonged survival suggest that this treatment can be effective. These findings will be used in the trial design for the next generation of drug, with reduced antigenicity and toxicity

Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients.

OBJECTIVE: To develop and validate practical prognostic models for death at 14 days and for death or severe disability six months after traumatic brain injury. DESIGN: Multivariable logistic regression to select variables that were independently associated with two patient outcomes. Two models designed: "basic" model (demographic and clinical variables only) and "CT" model (basic model plus results of computed tomography). The models were subsequently developed for high and low-middle income countries separately. SETTING: Medical Research Council (MRC) CRASH Trial. SUBJECTS: 10,008 patients with traumatic brain injury. Models externally validated in a cohort of 8509. RESULTS: The basic model included four predictors: age, Glasgow coma scale, pupil reactivity, and the presence of major extracranial injury. The CT model also included the presence of petechial haemorrhages, obliteration of the third ventricle or basal cisterns, subarachnoid bleeding, midline shift, and non-evacuated haematoma. In the derivation sample the models showed excellent discrimination (C statistic above 0.80). The models showed good calibration graphically. The Hosmer-Lemeshow test also indicated good calibration, except for the CT model in low-middle income countries. External validation for unfavourable outcome at six months in high income countries showed that basic and CT models had good discrimination (C statistic 0.77 for both models) but poorer calibration. CONCLUSION: Simple prognostic models can be used to obtain valid predictions of relevant outcomes in patients with traumatic brain injury

Radiographic Cortical Thickness Index Predicts Fragility Fracture in Gaucher Disease.

Background Patients with Gaucher disease (GD) have a high risk of fragility fractures. Routine evaluation of bone involvement in these patients includes radiography and repeated dual-energy x-ray absorptiometry (DXA). However, osteonecrosis and bone fracture may affect the accuracy of DXA. Purpose To assess the utility of DXA and radiographic femoral cortical thickness measurements as predictors of fragility fracture in patients with GD with long-term follow-up (up to 30 years). Materials and Methods Patients with GD age 16 years and older with a detailed medical history, at least one bone image (DXA and/or radiographs), and minimum 2 years follow-up were retrospectively identified using three merged UK-based registries (Gaucherite study, enrollment 2015-2017; Clinical Bone Registry, enrollment 2003-2006; and Mortality Registry, enrollment 1993-2019). Cortical thickness index (CTI) and canal-to-calcar ratio (CCR) were measured by two independent observers, and inter- and intraobserver reliability was calculated. The fracture-predictive value of DXA, CTI, CCR, and cutoff values were calculated using receiver operating characteristic curves. Statistical differences were assessed using univariable and multivariable analysis. Results Bone imaging in 247 patients (123 men, 124 women; baseline median age, 39 years; IQR, 27-50 years) was reviewed. The median follow-up period was 11 years (IQR, 7-19 years; range, 2-30 years). Thirty-five patients had fractures before or at first bone imaging, 23 patients had fractures after first bone imaging, and 189 patients remained fracture-free. Inter- and intraobserver reproducibility for CTI/CCR measurements was substantial (range, 0.96-0.98). In the 212 patients with no baseline fracture, CTI (cutoff, ≤0.50) predicted future fractures with higher sensitivity and specificity (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI: 0.84, 0.99; sensitivity, 92%; specificity, 96%) than DXA T-score at total hip (AUC, 0.78; 95% CI: 0.51, 0.91; sensitivity, 64%; specificity, 93%), femoral neck (AUC, 0.73; 95% CI: 0.50, 0.86; sensitivity, 64%; specificity, 73%), lumbar spine (AUC, 0.69; 95% CI: 0.49, 0.82; sensitivity, 57%; specificity, 63%), and forearm (AUC, 0.78; 95% CI: 0.59, 0.89; sensitivity, 70%; specificity, 70%). Conclusion Radiographic cortical thickness index of 0.50 or less was a reliable independent predictor of fracture risk in Gaucher disease. Clinical trial registration no. NCT03240653 © RSNA, 2022 Supplemental material is available for this article.This work was supported by a Stratified Medicine Program award, Gaucherite: MR/K015338/1 from the UKRI Medical Research Council (2013-2019) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (grant number IS-BRC-1215-20014) that in part supported SD and KP. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health and Social Care

Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial

Background: Adjuvant radiotherapy is effective treatment for stage I seminoma, but is associated with a risk of late non-germ-cell cancer and cardiovascular events. After good results in initial studies with one injection of carboplatin, we undertook a large randomised trial to compare the approaches of radiotherapy with chemotherapy in seminoma treatment.Methods: Between 1996 and 2001, 1477 patients from 70 hospitals in 14 countries were randomly assigned to receive radiotherapy (para-aortic strip or dog-leg field; n=904) or one injection of carboplatin (n=573; dose based on the formula 7×[glomerular filtration rate+25] mg), at two trial centres in the UK and Belgium. The primary outcome measure was the relapse-free rate, with the trial powered to exclude absolute differences in 2-year rates of more than 3%. Analysis was by intention to treat and per protocol. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN27163214.Findings: 885 and 560 patients received radiotherapy and carboplatin, respectively. With a median follow-up of 4 years (IQR 3·0–4·9), relapse-free survival rates for radiotherapy and carboplatin were similar (96·7% [95% CI 95·3–97·7] vs 97·7% [96·0–98·6] at 2 years; 95·9% [94·4–97·1] vs 94·8% [92·5–96·4] at 3 years, respectively; hazard ratio 1·28 [90% CI 0·85–1·93], p=0·32). At 2 years' follow-up, the absolute differences in relapse-free rates (radiotherapy–chemotherapy) were ?1·0% (90% CI ?2·5 to 0·5) by direct comparison of proportions, and 0·9% (?0·5 to 3·0) by a hazard-ratio-based approach. Patients given carboplatin were less lethargic and less likely to take time off work than those given radiotherapy. New, second primary testicular germ-cell tumours were reported in ten patients allocated irradiation (all after para-aortic strip field) and two allocated carboplatin (5-year event rate 1·96% [95% CI 1·0–3·8] vs 0·54% [0·1–2·1], p=0·04). One seminoma-related death occurred after radiotherapy and none after carboplatin.Interpretation: This trial has shown the non-inferiority of carboplatin to radiotherapy in the treatment of stage I seminoma. Although the absence of disease-related deaths and preliminary data indicating fewer second primary testicular germ-cell tumours favour carboplatin use, these findings need to be confirmed beyond 4 years' follow-up

Can p53 staining be used to identify patients with aggressive superficial bladder cancer?

Approximately 10% of patients with superficial bladder cancer (pTa/pT1) recur with life-threatening muscle-invasive disease. Identification of these patients has been a major goal of bladder cancer research. In 1994, it was suggested that p53 immunostaining could identify the cancers that would progress and it was proposed that tumours that stain for p53 should be treated aggressively with radiotherapy or cystectomy. Despite the hundreds of studies published since on the relationship between p53 and progression in superficial bladder cancer, the clinical utility of p53 immunostaining has not been resolved because of limitations concerning the numbers of patients and the length of follow-up. This study set out to overcome these limitations by using tissue from a large multicentre trial that recruited 502 patients with a median follow-up of 10 years. Each of 34 patients that had progressed with &gt;/= pT2 disease or had distant metastases or had died from bladder cancer was compared with one or two matched controls. Sections were stained with a mouse monoclonal antibody to p53, pAb1801. In agreement with many of the earlier studies, p53 immunostaining had prognostic significance. The adjusted hazard ratio for time to progression for the pAb1801-positive versus negative group was 2.5, with 95% confidence intervals of 1.05-5.98 (p = 0.039). The other major risk factor that is associated with progression of superficial bladder cancer is pT1G3 disease. Of the 42 pT1G3 cancers, 14 (33%) progressed. The proportion of cancers with p53 staining that progressed was similar to the proportion of pT1G3 cancers that progressed, but neither the sensitivity nor the specificity of association of p53 staining with progression is sufficient to recommend cystectomy in individual patients.</p