Drug Lit Exam 1- Crossover Studies

Front 1

cross over trial design (3)

Back 1

• Specialized type of controlled trial
• Each patient receives each treatment
• Compare treatments within the same patient rather than between patients

Front 2

how randomization is used in crossovers

Back 2

If randomization used, then randomize order of treatment, rather than to which treatment

Front 3

typical issues with RCT/crossover (not specific to crossover)( 4)

Back 3

– Sampling, inclusion/exclusion criteria
– Blinding- as in, is everyone blinded?
– Compliance
– Outcome measurement- always look at this; is this an established measure/approach

Front 4

Schematic of 2 x 2 crossover: describe

Back 4

Top line is period 1 and period 2
Group A: Treatment X--->then Y
Group B: Treatment Y--->Then X

Front 5

Key Factors that must be addressed for Effectiveness of Crossover Design (5)

Back 5

• Carryover and period effects on the outcome
• Treatment sequencing and patient assignment (is there carryover effect?)
• Crossover rules and timing of measurements
• Dropout, faulty data and other data problems
• Statistical analysis and sample size

Front 6

Order Effects in Crossover Trial (2)

Back 6

carryover effect
period effect

Front 7

carryover effect

Back 7

therapeutic effect carries over from one treatment to the next

Front 8

Things to avoid to minimize carryover effect (3)

Back 8

-avoid drugs with long half life (inadequate washout)

-pharmacological effects persisting after drug is eliminated

-conditioning or learned behavior that is part of the treatment? Maybe it's about some type of counseling/pt education-->can't wash this out as people don't forget what they learned (so not good design for that kind of thing)

Front 9

period effect

Back 9

the disease may progress, regress, or fluctuate in severity during the study- like tumors; just don't use this for crossovers

Front 10

Treatment Sequencing and Patient Assignment methods (4)

Back 10

1) Fixed sequence for all patients: A-B
2) Random assignment to sequence: A-B or B-A assigned by randomization
3) Deterministically balanced: A-B then B-A repeating to make sure equal numbers
4) Uncontrolled or haphazard

Front 11

fixed sequence properties (2)

Back 11

not ideal due to limited info on order effect- so you can't tell if there is an order effect i think, is what it's saying
–Simplest to carry out

Front 12

random assignment to a sequence- preference

Back 12

Most preferred since will take advantage of benefits of randomization

Front 13

When order effects are a risk , what is a way you can go about assigning sequences in a way that is non-universally accepted, but that might work?

Back 13

may use ABB, AAB, ABA, BAB or even 4 periods (use a bunch of periods (have to take treatment more than once)- too much burden, not liked)

Front 14

Timing of Measurements options (2)
blinding?

Back 14

time dependent cross over (e.g. after specific amt of time, 2 weeks, etc)- timing should be blinded when possible

disease state dependent crossover (e.g. after control of sx)

Front 15

Crossover Rules (2) regarding timing between measurements

Back 15

measurements may be delayed to allow for washout (may take days/weeks)

return to baseline before next treatment is desirable- sometimes not achieved

Front 16

dropouts and crossover trials (2)

Back 16

•Effects of dropouts on data analysis are magnified compared to parallel design
•Dropouts may be more common because of longer duration of trial

Front 17

how to avoid dropouts

Back 17

•Try to limit burden on subjects, while getting useful data

Front 18

sample size calculations in crossover trials vs other trials

Back 18

Sample size calculations similar to other trials with advantage of lower intra-subject variability since repeated observations made in same patient tend to be more similar than those made in different patients

Front 19

crossover sample size required vs. regular RCT
why?

Back 19

Even if no reduction in variability, the number of patients needed is less than parallel design because patients provide data for both groups

Front 20

statistical analysis of a crossover - how is it done (2)
indicate the power of first step

Back 20

•first test for treatment-time interactions (order effects), this is between groups and has relatively low power
–E.g. Group A Trtmnt X vs. Group B Trtmnt X

•Second, compare data from same patients over time: Trtmnt X vs. Trtmnt Y

Front 21

ways of comparing treatment X vs. T statistically (3)

Back 21

paired t-test, multivariate regression, analysis of variance

Front 22

Primary Advantages of Crossover Design (3)

Back 22

May use fewer patients, yet maintain power as you get more data from each subject (response to more than one treatment)

less variability
greater power with paired samples

Front 23

disadvantages of crossover design (3)

Back 23

•Sensitive to patient drop out and missing data and may decrease power if have dropouts – fewer cases for statistical tests

•Trial longer for each patient –Can contribute to missing data

Carryover effects or period effects may be difficult to assess – Need some type of washout period

Front 24

If carryover effect is likely, then is crossover design a good choice?

Back 24

no

Front 25

properties of appropriate Conditions and Treatments for Crossover (5)

Back 25

•Condition must be relatively stable
–More confident that difference are due to different treatments no disease variability

•Condition must not be “curable”

•Response to treatment should be rapid
–Will help limit subject burden

•Treatment effect should not be long lasting –Will give confidence that washout period will eliminate carryover effects

•Drop out rate should not be likely to be high (due to amplification of dropouts since you are missing twice the data per dropout)

Front 26

good diseases/types of studies for crossovers (4 disease states, 3 study types)

Back 26

•Pharmacokinetic studies
•Drug interaction studies
•Short term pharmacologic effects, e.g. acid production in the stomach
•Chronic pain
•Hypertension
•Diabetes
•Glaucoma

(chronic conditions that can be stabilized)

Front 27

poor examples for crossovers (5)

Back 27

•Peptic ulcer disease
•Depression
•Seasonal allergies
•Most infectious diseases
•Most types of cancer

Front 28

double dummy definition

Back 28

idea that one of the treatments needs 2 sprays and one doesn't- so they put a dummy second spray for drug that was one spray

Front 29

Don't have to worry about power if...

Back 29

findings were significant

Front 30

go over migraine study questions

Back 30

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