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Randomised Controlled Trials

Randomised Controlled Trials. What are RCTs?. “A study where people are allocated randomly to receiving a particular intervention or not (this could be two different treatments or one treatment and a placebo). This is the best type of study design to determine whether a treatment is effective.”

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Randomised Controlled Trials

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  1. Randomised Controlled Trials

  2. What are RCTs? “A study where people are allocated randomly to receiving a particular intervention or not (this could be two different treatments or one treatment and a placebo). This is the best type of study design to determine whether a treatment is effective.” www.nhs.uk/news/Pages/Newsglossary.aspx

  3. RCT setup Population Inclusion Criteria Sample Baseline Assessment Follow-up assessments

  4. The Hierarchy of Evidence

  5. Not all RCTs are created equal • Certain characteristics separate between good and bad trials – less or more prone to bias • Critically appraise the trial for: • Validity • Impact (size of the benefit) • Applicability

  6. Appraisal checklist - RAMMbo Internal validity – minimising biases Recruitment • Who did the subjects represent? Allocation • Was the assignment to treatments randomized? • Were the groups similar at the trial’s start? Maintenance • Were the groups treated equally? • Were outcomes ascertained & analyzed for most patients? Measurements • Were patients and clinicians “blinded” to treatment? OR • Were measurements objective & standardized? Study statistics (p-values & confidence intervals) Guyatt. JAMA, 1993

  7. BEST Central computer randomization DOUBTFUL Envelopes, etc Ensuring allocation concealment NOT RANDOMIZED Date of birth, alternate days, etc

  8. Appraisal checklist - RAMMbo Internal validity – minimising biases Recruitment • Who did the subjects represent? Allocation • Was the assignment to treatments randomized? • Were the groups similar at the trial’s start? Maintenance • Were the groups treated equally? • Were outcomes ascertained & analyzed for most patients? Measurements • Were patients and clinicians “blinded” to treatment? OR • Were measurements objective & standardized? Study statistics (p-values & confidence intervals) Guyatt. JAMA, 1993

  9. Apart from actual intervention - groups should receive identical care! Trial of Vitamin E given to pre-term infants (1948) ….Vitamin E seemed to "prevent" retrolental fibroplasia (blindness) (What actually happened? Frequently removing baby from 100% oxygen incubator to give them Vitamin E reduced their exposure the harmful high oxygen levels!) Effects of non-equal treatment

  10. Losses-to-follow-up How many is too many? “5-and-20 rule of thumb” • Small % probably leads to little bias • >20% poses serious threats to validity Depends on outcome event rate and comparative loss rates in the groups • Loss to follow-up rate should not exceed outcome event rate and should not be differential

  11. Intention-to-Treat Principle Maintaining the randomization Principle: • Once a patient is randomized, s/he should be analyzed in the group randomized to - even if they discontinue, never receive treatment, or crossover. Exception:If patient is found on BLIND reassessment to be ineligible based on pre-randomization criteria.

  12. Appraisal checklist - RAMMbo Internal validity – minimising biases Recruitment • Who did the subjects represent? Allocation • Was the assignment to treatments randomized? • Were the groups similar at the trial’s start? Maintenance • Were the groups treated equally? • Were outcomes ascertained & analyzed for most patients? Measurements • Were patients and clinicians “blinded” to treatment? OR • Were measurements objective & standardized? Study statistics (p-values & confidence intervals) Guyatt. JAMA, 1993

  13. Measurement Bias • Blinding – Who? • Participants? • Investigators? • Outcome assessors? • Analysts? • Most important to use "blinded" outcome assessors when outcome is not objective! • Papers should report WHO was blinded and HOWit was done

  14. Appraisal checklist - RAMMbo Internal validity – minimising biases Recruitment • Who did the subjects represent? Allocation • Was the assignment to treatments randomized? • Were the groups similar at the trial’s start? Maintenance • Were the groups treated equally? • Were outcomes ascertained & analyzed for most patients? Measurements • Were patients and clinicians “blinded” to treatment? OR • Were measurements objective & standardized? Study statistics (p-values & confidence intervals) Placebo Effect or Chance or Real Effect Guyatt. JAMA, 1993

  15. Assessing the role of chance • P-values • use statistical test to examine the ‘null’ hypothesis • associated with “p values” - if p<0.05 then result is statistically significant • Confidence Intervals • estimates a range of values that is likely to include the true value

  16. RCT for everything? • Controlled clinical trials are viewed as the “gold standard” • However, it is not always be best to perform an RCT • unnecessary • inappropriate • impossible • inadequate

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