59 60 Patients screened for eligibility Excluded Randomized Control Analysis of

59 60 patients screened for eligibility excluded

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60Patients screened for eligibilityExcluded:-...Randomized ControlAnalysis of outcomesIs the treatment effective? First, compare against …- No intervention-Placebo- Waiting list- Sham treatmentOpen Forum Infect Dis. 2016 Jan 29;3(1):ofw011
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Sham treatment – placebo effect and ethicsExamples from surgical and medical device research:Trial of fetal tissue transplantation into the brain for Parkinson’s diseaseSham group: drilled holes in foreheadNo treatment effect beyond the placebo effectTrial of bone cement injected into fractured vertebrae for treatment of compression fractures (“vertebroplasty”)Sham group: surgical procedureNo treatment effect beyond the placebo effectUp to 58% of patients may respond to sham surgery!61Redberg RF. NEJM. 2014;371:892-3
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Think about what to offer the “control group”62
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Do explanatory trials until evidence “clear”63No differenceYeast superiorControl superiorLarge differenceDifference: Incidence of AADLarge differenceTrial 1+ Trial 2+ Trial 3+ Trial 4+ Trial 5+ Trial 6+ Trial 7
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Active learning64Why do early trials tend to show larger effect estimates than later trials?Talk to your neighbor …
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65The next stage: Comparative effectiveness trialsRandomizedInvestigate superiority or equivalence/non-inferiority Yeast + ABBacteria + AB
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66Some types of randomized trials
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Factorial 2x2 design67Test A+BTest ATest BControlYesNoYesNoTest ABeta-carotenePlaceboTotalAspirin5519551811,037Placebo5517551711,034Total11,03811,03522,071
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Equivalence and non-inferiority trials68Non-inferioritytrial is designed to show that test intervention is not inferior to the comparison (by a pre-stated margin of non-inferiority ∆)Equivalencetrial is designed to show that test intervention is equivalent to comparison (with equivalence defined as the treatment effect being between - ∆ and ∆)Analysis based on confidence intervals (e.g. 95% CI)
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Equivalence and non-inferiority trials69Superiority trial:Null hypothesis: No difference between treatment groupsAlternative hypothesis: Treatment effects differ between groupsNon-inferiority trial:Null and alternative hypotheses are reversed Example for a null hypothesis in a non-inferiority trial: New treatment is worse than old by ≥ ∆
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Scenarios in a non-inferiority trial70N Engl J Med 2017;377:1357-67A.)B.)C.)D.)E.)
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Cluster design71Unit of randomization is a group, not an individualUsefulwheninterventioncannotbeeasilyisolated, e.g. particular hygiene measures on ahospital wardNeed to account for correlation within clusters inanalysis
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72Cross-over trialsPatients screened for eligibilityExcluded:-...Randomized ControlMeasurement of outcomes wash out periodInterventionInterventionControlMeasurement and analysis of outcomesPeriod 1Period 2
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73Advantages of cross-over trialsEach subject serves as her/his own controlTheoretically, controls ideally for confounding and comes, ofall study designs, closest to exchangeabilityTheoretically, very efficient (sample size requirements about70% of a two-arm parallel group trial)
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  • Epidemiology, Clinical trial, Randomized controlled trial, Coronary artery bypass surgery, Crossover study

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