Clinical Trials

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❘❙❚■ Chapter 7 | RandomizationThe balance forced by blocking is especially important in long-term trials if:• recruitment is slow• the type of patients recruited in the trial changes during theenrollment period• the trial may be stopped early for safety or efficacy reasons• routine practice changes for patients in both groups during the trialThe only disadvantage of blocking is that every fourth patient, and occasionallyevery third patient (when the sequence is AABB or BBAA), becomes predictableif the treatments are not masked and the previous allocations of that blockare known.Stratified randomizationStratified randomization takes the balance correction suggested by blocking onestep further. Not only are the numbers with treatments A and B balancedperiodically, but a balance is also constantly maintained for a set of predeterminedimportant factors that may impact on the prognosis of the patient, such as age,gender, diabetes, severity of illness, or geography. If prognostic factors are notevenly distributed between treatment groups it can give the investigator cause forconcern, although statistical methods, such as the Cox regression model, areavailable that allow for such a lack of comparability.ExampleStratified randomization is implemented in three steps. We can illustrate theprocedures using the CF-WISE (Withdrawal of Inhaled Steroids EvaluationStudy in Patients with Cystic Fibrosis) trial conducted at the Clinical Trials andEvaluation Unit of the Royal Brompton Hospital, London, UK. CF-WISE wasa randomized placebo-controlled trial designed to test the feasibility and safetyof periodically withdrawing inhaled corticosteroids (ICS) in 240 children andadults with cystic fibrosis who were already taking ICS. The two treatmentstrategies involved a return to either ICS treatment after withdrawal (A) or toplacebo (B). The primary endpoint was the time to first respiratory exacerbation.Step 1:Choose the prognostic factors that could impact on the primary endpoint.Experience of earlier trials and literature show that atopy, forcedexpiratory volume within 1 second (FEV 1), and age are the mostimportant determinants of time to first respiratory exacerbation.70
Clinical Trials: A Practical Guide ■❚❙❘Table 3. Strata definitions for the CF-WISE (Withdrawal of Inhaled Steroids Evaluation Study in Patientswith Cystic Fibrosis) study show three factors for stratification.Stratum Atopy FEV 1(%) Age (years) Randomization1 Positive 40–60
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❘❙❚■ ContributorsStephen L
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Clinical Trials: A Practical Guide
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■■❚❙❘Part IIIBasics ofSta
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■■❚❙❘Chapter 19Comparison
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■■❚❙❘Part IVSpecial Trial
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■■❚❙❘Chapter 23Subgroup A
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■■❚❙❘Chapter 24Regression
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■■❚❙❘Chapter 25Adjustment
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■■❚❙❘GlossaryGlossary453
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■■❚❙❘IndexIndex467
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Clinical Trials

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