Assessment of Rescue Medication Effect

in Psychiatric Clinical Trials

Zhibao Mi, John H. Krystal, Karen M. Jones, Robert A. Rosenheck, Joseph F. Collins and Ying Lu

VA Cooperative Studies Program

VA Connecticut Healthcare Systems

Yale School of Medicine

Stanford University School of Medicine

Society for Clinical Trials 36th Annual Meeting

Background

Rescue Medication

Worsening Symptoms Insufficient Treatment Response

Not Defined in the Protocol

Dropout

Data Missing Issue

Compromise Inference

Statistical Tradeoff

Defined in the Protocol

Treatment Bias Excluded from Analysis

Often Times, Non-randomized Medications Used in Clinical Trials

Missing Reduction Additional Variation Confounding Effect

Power Issue

To Discuss Rescue Medication Effect via a Psychiatric Clinical Trial

due to

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Risperidone Trial

A Double Blinded Placebo Controlled Randomized Multicenter Clinical Trial to

Test Risperidone for PTSD Treatment

296 randomized

147 randomized to Risperidone 149 randomized to Placebo

145 received Risperidone 2 lost follow-up 147 received Placebo 2 lost follow-up

12 with no baseline

123 completed study 10 discontinued study 124 completed study

133 with valid baseline 13 with no baseline 134 with valid baseline

10 discontinued study

Primary endpoint: between treatment difference in Clinician-Administrated PTSD Scale (CAPS)

Repeated measurements at baseline, weeks 6, 12, and 24

Missing primarily due to dropouts

Rescue medication to control adverse effect

32 rescue medication 26 rescue medication

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Percentage of Subjects Rescued Over Time

Placebo (26) 0 0 1 4 2 3 8 7 0 1

Risperidone (32) 0 2 5 5 3 4 6 4 3 0

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Rescue Medication

Treatment Outcome

Statistical Issues

Confounding Effect

Testing Efficiency

Tradeoff Rescue Dropout Power

Rescue Variation Power

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Statistical Models

Basic Model

01 ijijjij yT

ijiijij uy

For a random intercepts model

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Statistical Models

Rescue Model

ijiiijijij vuRy

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Association of Rescue with Outcome and Treatment

Treatment vs. Rescue Medication Rescue Medication vs. Outcome Treatment vs. Outcome

Coefficient p Coefficient p Coefficient p

0.06 0.0862 9.84 <0.0001 4.25 0.0694

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Impact of Rescue Medication on Treatment Effect

Rescue Med Included Rescue Med Excluded Rescue Med Censored

Coefficient p Coefficient p Coefficient p

Treatment Effect 4.25 0.0694 5.45 0.0320 5.99 0.0157

Rescue medication use was ignored

Subjects excluded from the analysis once rescue medication was used

Data points included in the analysis before subjects were on rescue medication

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Time to Rescue Medication

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log-Rank test: p = 0.2957

Time to Rescue Medication as an Endpoint

Analyses Stratified on Rescue Medication

Overall All Rescue Medication No Rescue Medication

Coefficient p Coefficient p Coefficient p

Treatment Effect 4.25 0.0694 2.10 0.6831 5.45 0.0320

Stratification Analysis

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Adjusted on Rescue Medication

Rescue Med (Yes/No) Rescue Med on Weeks

Coefficient p Coefficient p

Treatment Effect 4.71 0.0380 4.67 0.0412

Rescue Effect 8.69 0.0001 0.49 0.0023

Adjustment of Rescue Medication

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Sensitivity Analysis

Re

scu

e M

ed

(Y

es/N

o)

Re

scu

e M

ed

on

We

eks

LS Mean Difference Treatment Coefficient

If effect of rescue medication were known, or could be estimated, or were believed to

lie in a certain range, then the underlying outcome could be estimated and analyzed as

if it were the observed outcome

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Confidence Intervals of Treatment Coefficients

Simulations for Treatment Effect

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Testing Efficiency (Modeling and Simulations)

Dropout and Rescue Model

Let ( ijX , ijR ) be vector of (0, 1) variables: ijX be a binary indicator of observing in the study (=1); ijR be

the indicator of the thi patient receiving rescue medication (=1) in the thj visit to reduce the chance of

being a dropout

i

jij qXP 1)1(

j

R

ijjiij qeRXXP ij ),1|0( )1(

1),0|0( )1( ijjiij RXXP

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Time

Rescue Non-rescue

Dropout No dropout Overall Dropout No dropout Overall

6 week 1(4.5%) 21 22 10 (4.1%) 235 245

12 week 1(2.3%) 42 43 12(5.3%) 212 224

24 week 3(5.2%) 55 58 17 (8.1%) 192 209

Log-linear Model - 0.4658 ( p = 0.1691)

Rescue medication effect on subject dropout ()

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Log-linear Model to Estimate Using the Trial Data

Role of in Dropout Reduction

(%)

0.0 -0.1 -0.5 -1.0 -2.0 -3.0

10 10 9 6 4 1 0

15 15 14 9 6 2 1

20 20 18 12 7 3 1

25 25 23 15 9 3 1

30 30 27 18 11 4 1

Time

(week)

Dropout Rate (%) based on Data Dropout Rate (%) based on

No Rescue Rescue Difference 0.00 -0.10 -0.15 -0.50

6 4.78 4.48 0.30 4.78 4.33 4.11 2.90

12 5.74 4.48 1.26 5.74 5.19 4.94 3.48

24 8.13 7.46 0.67 8.13 7.36 7.00 4.93

jq

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Effect of Rescue Medication on Sample Size

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Effect of Rescue Medication on Variation

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Effect of Rescue Medication on Power

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Summary

Rescue Medication

To Avoid

Analysis Phase

Defined It in the Protocol

Design Phase

Test Efficiency Confounding Effect

Inevitable

Check Correlations

No Correlations Correlations

Standard Analysis Stratified Analysis Adjusted in the Model

Sensitivity Analysis to

Assess Rescue Effect

Simulation to Assess

Bias

Additional Variation

Power Assessment

Define Rescue

Criteria

Assess Rescue

Impact

Simulations for

Variation, Bias

Rescue

Threshold

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Thank You

Society for Clinical Trials 36th Annual Meeting

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