The intention-to-treat approach in randomized controlled trials: Are authors saying what they do and doing what they say?

Survival of pediatric acute myeloid leukemia (AML) has improved considerably over the past decades. Since 1985, allogeneic stem cell transplantation (allo-SCT) is widely recommended for patients who have a matched sibling donor. However, it remains controversial whether allo-SCT is superior to chemotherapy for children with newly diagnosed AML. This review summarizes phase 3 clinical trials that compared allo-SCT with chemotherapy (including autologous SCT) in pediatric AML, excluding studies that did not use the intention-to-treat analysis or correct for time-to-transplantation. Although allo-SCT might prevent more relapses than chemotherapy, the number needed for transplantation (with allo-SCT) to prevent one relapse is in the order of 10 patients. Moreover, overall survival is similar with both methods in most recent studies, apparently because of increased salvagability of a relapse when initial therapy concerned chemotherapy only, and because of a higher treatment-related mortality with allo-SCT. Because allo-SCT also gives more severe side effects and results more often in secondary malignancies than chemotherapy, we do not recommend allo-SCT in first remission for pediatric AML in general. Further research should focus on the possibility that subgroups might benefit from allo-SCT, aiming at further improvements in the prognosis of pediatric AML. (Blood. 2010;116(13):2205-2214)

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“…8 Subsequently, in some studies the rules of the intention-to-treat analysis were not followed correctly. 48,49 …”

Section: Discussionmentioning

confidence: 99%

A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia

Niewerth

Creutzig

Bierings

et al. 2010

Blood

117

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“…107,108 Treatment was dealt with 'as randomised'. Demographics and baseline characteristics summaries were provided for the ITT population.…”

Section: Analysis Populationmentioning

confidence: 99%

The feasibility of early pulmonary rehabilitation and activity after COPD exacerbations: external pilot randomised controlled trial, qualitative case study and exploratory economic evaluation

Cox

O’Connor

Biggs

et al. 2018

Health Technol Assess

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BackgroundChronic obstructive pulmonary disease (COPD) affects > 3 million people in the UK. Acute exacerbations of COPD (AECOPD) are the second most common reason for emergency hospital admission in the UK. Pulmonary rehabilitation is usual care for stable COPD but there is little evidence for early pulmonary rehabilitation (EPR) following AECOPD, either in hospital or immediately post discharge.ObjectiveTo assess the feasibility of recruiting patients, collecting data and delivering EPR to patients with AECOPD to evaluate EPR compared with usual care.DesignParallel-group, pilot 2 × 2 factorial randomised trial with nested qualitative research and an economic analysis.SettingTwo acute hospital NHS trusts. Recruitment was carried out from September 2015 to April 2016 and follow-up was completed in July 2016.ParticipantsEligible patients were those aged ≥ 35 years who were admitted with AECOPD, who were non-acidotic and who maintained their blood oxygen saturation level (SpO2) within a prescribed range. Exclusions included the presence of comorbidities that affected the ability to undertake the interventions.Interventions(1) Hospital EPR: muscle training delivered at the patient’s hospital bed using a cycle ergometer and (2) home EPR: a pulmonary rehabilitation programme delivered in the patient’s home. Both interventions were delivered by trained physiotherapists. Participants were allocated on a 1 : 1 : 1 : 1 ratio to (1) hospital EPR (n = 14), (2) home EPR (n = 15), (3) hospital EPR and home EPR (n = 14) and (4) control (n = 15). Outcome assessors were blind to treatment allocation; it was not possible to blind patients.Main outcome measuresFeasibility of recruiting 76 participants in 7 months at two centres; intervention delivery; views on intervention/research acceptability; clinical outcomes including the 6-minute walk distance (6WMD); and costs. Semistructured interviews with participants (n = 27) and research health professionals (n = 11), optimisation assessments and an economic analysis were also undertaken.ResultsOver 7 months 449 patients were screened, of whom most were not eligible for the trial or felt too ill/declined entry. In total, 58 participants (76%) of the target 76 participants were recruited to the trial. The primary clinical outcome (6MWD) was difficult to collect (hospital EPR,n = 5; home EPR,n = 6; hospital EPR and home EPR,n = 5; control,n = 5). Hospital EPR was difficult to deliver over 5 days because of patient discharge/staff availability, with 34.1% of the scheduled sessions delivered compared with 78.3% of the home EPR sessions. Serious adverse events were experienced by 26 participants (45%), none of which was related to the interventions. Interviewed participants generally found both interventions to be acceptable. Home EPR had a higher rate of acceptability, mainly because patients felt too unwell when in hospital to undergo hospital EPR. Physiotherapists generally found the interventions to be acceptable and valued them but found delivery difficult because of staffing issues. The health economic analysis results suggest that there would be value in conducting a larger trial to assess the cost-effectiveness of the hospital EPR and hospital EPR plus home EPR trial arms and collect more information to inform the hospital cost and quality-adjusted life-year parameters, which were shown to be key drivers of the model.ConclusionsA full-scale randomised controlled trial using this protocol would not be feasible. Recruitment and delivery of the hospital EPR intervention was difficult. The data obtained can be used to design a full-scale trial of home EPR. Because of the small sample and large confidence intervals, this study should not be used to inform clinical practice.Trial registrationCurrent Controlled Trials ISRCTN18634494.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 11. See the NIHR Journals Library website for further project information.

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“…The use and reporting of ITT and PP methods in both the human42, 46, 47 and veterinary3, 4, 5, 6, 7, 8, 9, 13 medical literature varies widely. In many studies, key pieces of information, including original number of patients recruited and randomized, how missing data was treated, and exactly which analysis methods and data sets were used, are lacking 48, 49.…”

Section: Analysis Of Patient Populations With Missing Outcome Datamentioning

confidence: 99%

Clinical Trials in Veterinary Medicine: A New Era Brings New Challenges

Oyama

Ellenberg

Shaw

2017

Veterinary Internal Medicne

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Randomized clinical trials (RCTs) are among the most rigorous ways to determine the causal relationship between an intervention and important clinical outcome. Their use in veterinary medicine has become increasingly common, and as is often the case, with progress comes new challenges. Randomized clinical trials yield important answers, but results from these studies can be unhelpful or even misleading unless the study design and reporting are carried out with care. Herein, we offer some perspective on several emerging challenges associated with RCTs, including use of composite endpoints, the reporting of different forms of risk, analysis in the presence of missing data, and issues of reporting and safety assessment. These topics are explored in the context of previously reported veterinary internal medicine studies as well as through illustrative examples with hypothetical data sets. Moreover, many insights germane to RCTs in veterinary internal medicine can be drawn from the wealth of experience with RCTs in the human medical field. A better understanding of the issues presented here can help improve the design, interpretation, and reporting of veterinary RCTs.

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The intention-to-treat approach in randomized controlled trials: Are authors saying what they do and doing what they say?

Abstract: This study emphasizes that authors use the label ;intention-to-treat' quite differently. The most common use refers to the analysis of all available subjects as randomized regardless of the missing data aspect.

Cited by 113 publications

References 33 publications

A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia

A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia

The feasibility of early pulmonary rehabilitation and activity after COPD exacerbations: external pilot randomised controlled trial, qualitative case study and exploratory economic evaluation

Clinical Trials in Veterinary Medicine: A New Era Brings New Challenges

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