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David J Torgerson - One of the best experts on this subject based on the ideXlab platform.

  • What is Special About Randomisation
    Designing Randomised Trials in Health Education and the Social Sciences, 2020
    Co-Authors: David J Torgerson, Carole Torgerson
    Abstract:

    The main difference between other study design methods and the randomised controlled trial is that in the latter two or more groups are formed by random allocation. Randomisation is the best approach to dealing with and controlling for selection bias, regression to the mean and temporal changes. Other issues, such as blinding, or the use of placebos, may be associated with some types of randomised trial but their use is neither a necessary nor a sufficient condition for a study to be identified as a randomised trial.

  • The use of unequal Randomisation in clinical trials — An update
    Contemporary Clinical Trials, 2015
    Co-Authors: Emily Peckham, Jo C Dumville, Sally Brabyn, Liz Cook, Thomas Devlin, David J Torgerson
    Abstract:

    Abstract Objective To update a 2005 review of the reasons researchers have given for the use of unequal Randomisation in randomised controlled trials (RCTs). Main measures Intervention being tested; type of study; number of participants; Randomisation ratio; sample size calculation and reason given for using unequal Randomisation. Methods Review of trials using unequal Randomisation. Databases and sources Cochrane library, Medline and CINAHL. Results A total of 86 trials were identified. Of these 82 trials (95%) recruited patients in favour of the experimental group. Various reasons for the use of unequal Randomisation were given including: gaining treatment experience; identification of adverse events; ethical; logistic and enhancing recruitment. No trial reported explicitly used it for cost-effectiveness. Most of the papers (i.e. 47, 55%) did not state why they had used unequal Randomisation and only 38 trials (44%) appeared to have taken the unequal Randomisation into account in their sample size calculation. Conclusion Most studies did not mention the rationale for unequal allocation, and a significant proportion did not appear to account for it in the sample size calculations. Unlike the previous review economic considerations were not stated as a rationale for its use. A number of trials used it to enhance recruitment, although this has not been tested.

  • Is restricted Randomisation necessary
    BMJ, 2006
    Co-Authors: Catherine Hewitt, David J Torgerson
    Abstract:

    Restrictions during Randomisation make it easier for investigators to guess the next allocation. Statistical correction of any imbalance in confounders at the end of the study is equally accurate for most trials and would be safer Randomised controlled trials commonly use some form of restriction when allocating participants—for example, blocking, stratification, or minimisation.1 2 The main reason is to achieve a better balance of known confounders. For an individual trial simple Randomisation may lead to some chance imbalances on some variables. These imbalances are unimportant if the variables have a weak relation with the outcome. However, if by chance the groups differ at baseline on one or more confounding variables, the trial result may be misleading; this effect could be in either direction. Stratification and minimisation are used to reduce these chance imbalances. Blocking needs to be used in combination with stratification to ensure that roughly equal numbers of participants are randomised to each of the treatments in the individual strata.1 Otherwise, it is statistically equivalent to using simple Randomisation. However, using restricted Randomisation can generate its own problems. Introducing any form of restricted Randomisation increases the risk of subversion (conscious or unconscious) and technical error. Most examples of known subversion relate to situations where allocation sequences are public knowledge or the concealment of the allocation is inadequate, such as using sealed envelopes that can be tampered with.3 4 However, this type of subversion is not specific to restricted Randomisation. ![][1] What will come next? Credit: PHOTOS.COM With restricted Randomisation subversion remains possible even when adequate precautions have been taken to conceal the Randomisation sequence.5 In an open trial, if we know the block size and we keep a record of previous allocations then we will always be certain about the last allocation in the block. Furthermore, … [1]: /embed/graphic-1.gif

  • the use of unequal Randomisation ratios in clinical trials a review
    Contemporary Clinical Trials, 2006
    Co-Authors: Jo C Dumville, Seokyung Hahn, Jeremy N V Miles, David J Torgerson
    Abstract:

    Abstract Objective To examine reasons given for the use of unequal Randomisation in randomised controlled trials (RCTs). Main Measures Setting of the trial; intervention being tested; Randomisation ratio; sample size calculation; reason given for Randomisation. Methods Review of trials using unequal Randomisation. Databases and sources Cochrane library, Medline, Pub Med and Science Citation Index. Results A total of 65 trials were identified; 56 were two-armed trials and nine trials had more than two arms. Of the two-arm trials, 50 trials recruited patients in favour of the experimental group. Various reasons for the use of unequal Randomisation were given. Six studies stated that they used unequal Randomisation to reduce the cost of the trial, with one screening trial limited by the availability of the intervention. Other reasons for using unequal allocation were: avoiding loss of power from drop-out or cross-over, ethics and the gaining of additional information on the treatment. Thirty seven trials papers (57%) did not state why they had used unequal Randomisation and only 14 trials (22%) appeared to have taken the unequal Randomisation into account in their sample size calculation. Conclusion Although unequal Randomisation offers a number of advantages to trials the method is rarely used and is especially under-utilised to reduce trial costs. Unequal Randomisation should be considered more in trial design especially where there are large differences between treatment costs.

  • Use of unequal Randomisation to aid the economic efficiency of clinical trials
    BMJ, 2000
    Co-Authors: David J Torgerson, Marion K Campbell
    Abstract:

    This is one of an occasional series of notes on economics In an earlier note we showed how economic criteria can help in sample size calculations by defining clinical endpoints of economic importance.1 However, there is a further issue concerning sample size calculations where economic information may be useful—the Randomisation ratio. Most randomised trials allocate equal numbers of patients to experimental and control groups. 2 3 This is the most statistically efficient Randomisation ratio as it maximises statistical power for a given total sample size. However, this may not be the most economically efficient Randomisation ratio.4 When two or more treatments under evaluation have a cost difference it may be more economically efficient to randomise fewer …

N. Klar - One of the best experts on this subject based on the ideXlab platform.

Andres J M Ferreri - One of the best experts on this subject based on the ideXlab platform.

  • whole brain radiotherapy or autologous stem cell transplantation as consolidation strategies after high dose methotrexate based chemoimmunotherapy in patients with primary cns lymphoma results of the second Randomisation of the international extranod
    The Lancet Haematology, 2017
    Co-Authors: Andres J M Ferreri, Kate Cwynarski, Elisa Jacobsen Pulczynski, Valter Torri, Paul La Rosee, Elisabeth Schorb, Mascha Binder, Alberto Fabbri, Eleonora Minacapelli, Monica Falautano
    Abstract:

    Summary Background The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first Randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second Randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy. Methods HIV-negative patients (aged 18–70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0–3 were randomly assigned to receive four courses of methotrexate 3·5 g/m 2 on day 1 plus cytarabine 2 g/m 2 twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m 2 on days −5 and 0 (group B); or the same methotrexate–cytarabine–rituximab combination plus thiotepa 30 mg/m 2 on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second Randomisation between WBRT (photons of 4–10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine–thiotepa conditioned ASCT (carmustine 400 mg/m 2 on day −6, and thiotepa 5 mg/kg every 12 h on days −5 and −4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both Randomisations, and a computer-generated Randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920. Findings Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second Randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70–90) in group D and 69% (59–79) in group E (hazard ratio 1·50, 95% CI 0·83–2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT. Interpretation WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision. Funding Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.

  • chemoimmunotherapy with methotrexate cytarabine thiotepa and rituximab matrix regimen in patients with primary cns lymphoma results of the first Randomisation of the international extranodal lymphoma study group 32 ielsg32 phase 2 trial
    The Lancet Haematology, 2016
    Co-Authors: Andres J M Ferreri, Kate Cwynarski, Elisa Jacobsen Pulczynski, Maurilio Ponzoni, Martina Deckert, Letterio S Politi, Valter Torri, Paul La Rosee, Elisabeth Schorb, Achille Ambrosetti
    Abstract:

    Summary Background Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate–cytarabine combination therapy (the MATRix regimen), followed by a second Randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first Randomisation in this Article. Methods For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18–70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m 2 on day 1 plus cytarabine 2 g/m 2 twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m 2 on days −5 and 0 (group B); or the same methotrexate–cytarabine–rituximab combination plus thiotepa 30 mg/m 2 on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both Randomisations, and a computer-generated Randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first Randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920. Findings Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22–38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38–60), compared with 23% (14–31) of those treated with methotrexate–cytarabine alone (hazard ratio 0·46, 95% CI 0·28–0·74) and 30% (21–42) of those treated with methotrexate–cytarabine plus rituximab (0·61, 0·40–0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate–cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3–4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity. Interpretation With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials. Funding Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

Maria Timofeeva - One of the best experts on this subject based on the ideXlab platform.

  • physical activity and colorectal cancer risk a two sample mendelian Randomisation study
    The Lancet, 2019
    Co-Authors: Xiaomeng Zhang, Evropi Theodoratou, Xue Li, Susan M Farrington, Victoria Svinti, Harry Campbell, Malcolm G Dunlop, Maria Timofeeva
    Abstract:

    Abstract Background Evidence from observational studies suggests a protective role for physical activity against colorectal cancer risk. However, whether the observed association is causal or not is not clear. We did a two sample Mendelian Randomisation study to examine the causal relationship between physical activity and colorectal cancer risk. Methods This Mendelian Randomisation study used common genetic variants associated with self-reported physical activity and accelerometer-based physical activity as instrumental variables. These variables were derived from the largest available genome-wide association study of physical activity, namely, UK Biobank. The effect of the instrumental variables for physical activity was analysed in a large colorectal cancer risk genome-wide association study using summary level data that included 31 197 cases and 61 770 controls. We applied inverse variance-weighted method as the main analysis method, with Mendelian Randomisation-Egger, Mendelian Randomisation–pleiotropy residual sum and outlier, Mendelian Randomisation-robust, leave-one-out method, mode-based estimate, and the median-based method as sensitivity analyses. Findings Our results show a significant protective effect between accelerometer-based physical activity and colorectal cancer risk (the outlier-adjusted odds ratios [OR] of inverse variance-weighted Mendelian Randomisation was 0·92 per one standard deviation increase of accelerometer-base physical activity (95% CI 0·87–0·98, p=0·0137). The effect between self-reported physical activity and colorectal cancer risk was not statistically significant but was supportive of an inverse association (the outlier-adjusted OR of inverse variance-weighted Mendelian Randomisation was 0·61 per 1 SD increase of moderate-to-vigorous physical activity [95% CI 0·36–1·06, p=0·0783]). Interpretation The findings of this large Mendelian Randomisation study show, for the first time to our knowledge, that objectively measured physical activity is causally implicated in reducing colorectal cancer risk. It suggests that physical activity is not merely a biomarker of good health. The limitations of the study are that it is based on only two genetic instruments and that it has limited power, despite the study size. Nonetheless, at a population level, these findings provide strong reinforcing evidence to support public health policy measures that encourage exercise, even in obese individuals. Funding This work was supported by cancer research UK programme grant C348/A18927 (MD). ET is supported by a cancer research UK Career Development Fellowship (C31250/A22804). XZ has a PhD studentship from The Darwin Trust of Edinburgh.

Anton Donner - One of the best experts on this subject based on the ideXlab platform.

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