Bhargava Kandala

Department of Pharmaceutics
College of Pharmacy , UF
Design and Analysis of Crossover
Study Designs
Crossover Study
Treatments administered in a sequence to each
experimental unit over a set of time periods.
Comparison of treatments on a within-subject
level.
Increased precision of treatment comparisons.
A treatment given in one period might influence
the response in the following treatment period
residual/carryover effect
Baseline values Can be included as covariates
to increase the precision

Study Design
Single center, double blind, randomized, 3 period,
3 treatment, 3 sequence crossover study
Randomization
Low
Medium
High
Low
Medium
High
Low
Medium
High
Washout

Washout

Subjects = 10
Baseline 1
Period 1 (q.d.)


Period 2 (q.d.)
Period 3 (q.d.)
Baseline 2
Baseline 3
PD Measurements
PD Measurements PD Measurements
1 Week 1 Week 5 days 5 days 5 days
Model for Crossover Design

Period 1 2 3 4 5 6
I A B C A B C
II B C A C A B
III C A B B C A
proc glm data = allperiodanaly;
class sequence subject period trt;
model fenoav = sequence
subject(sequence) period trt/solution;
random subject(sequence);
run;
proc mixed data = allperiodanaly;
class sequence subject period trt;
model fenoav = sequence period trt;
random subject(sequence);
lsmeans trt/ pdiff cl;
run;
Baseline
Baseline - Covariate
Average baseline
values not
significantly different
Presence of
significant carryover
effects (p-value <
0.05)
70
75
80
1 2 3
B
a
s
e
l
i
n
e

A
v
e
r
a
g
e

Period
Baseline Average by
Period
No Covariate Analysis of
Covariance (ANCOVA)
Baseline Treatment
= 0 = Model Estimate =1
Baseline is not used as
a covariate
Baseline values are
treated as a
quantitative variable
By taking the simple
difference the value of
is forced to be 1
Carryover Effect





* Covariates tested for carryover;
proc mixed data = allperiodanaly;
class sequence subject period trt;
model fenoav = sequence period fenob trt
carry1 carry2;
random subject(sequence);
lsmeans trt/ pdiff cl e;
run;
Results







cannot be forced to be 1
Parameter No Covariate Analysis of
Covariance
(ANCOVA)
Baseline
Treatment
0 0.38 1
Residual
Variability
85.39 67.02 180.02
Carryover
Effect
Not significant
(p-value >0.05)
Not Significant
(p-value>0.05)
Significant
Results

Parameter No Covariate Analysis of

Covariance
(ANCOVA)
Baseline
Treatment
0 0.38 1
Residual
Variability
85.39 67.02 180.02
Carryover
Effect
Not significant
(p-value >0.05)
Not Significant
(p-value>0.05)
Significant
Results






Reduced impact of the baseline values while
using ANCOVA can explain the absence of
carryover effects
Parameter No Covariate Analysis of
Covariance
(ANCOVA)
Baseline
Treatment
0 0.38 1
Residual
Variability
85.39 67.02 180.02
Carryover
Effect
Not significant
(p-value >0.05)
Not Significant
(p-value>0.05)
Significant
Conclusions
Day 5 data suitable for analysis
Maximum dose resolution
No carryover effect

Baseline adjustment
Simple difference increases the variability and
introduces carryover effects
ANCOVA is the preferred method

Crossover design model with baseline values as
covariates will be used for future simulations

Patient Sequence Period 1 Period 2 Period 3
1 FSP 3500 3200 2900
10 FSP 3400 2800 2200
17 FSP 2300 2200 1700
21 FSP 2300 1300 1400
23 FSP 3000 2400 1800
4 SPF 2200 1100 2600
8 SPF 2800 2000 2800
16 SPF 2400 1700 3400
6 PFS 2200 2500 2400
9 PFS 2200 3200 3300
13 PFS 800 1400 1000
20 PFS 950 1320 1480
26 PFS 1700 2600 2400
31 PFS 1400 2500 2200
2 FPS 3100 1800 2400
11 FPS 2800 1600 2200
14 FPS 3100 1600 1400
19 FPS 2300 1500 2200
25 FPS 3000 1700 2600
28 FPS 3100 2100 2800
3 SFP 2100 3200 1000
12 SFP 1600 2300 1600
18 SFP 1600 1400 800
24 SFP 3100 3200 1000
27 SFP 2800 3100 2000
5 PSF 900 1900 2900
7 PSF 1500 2600 2000
15 PSF 1200 2200 2700
22 PSF 2400 2600 3800
30 PSF 1900 2700 2800