Society for Clinical Trials 36 th Annual Meeting 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
Background Often Times, Non-randomized Medications Used in Clinical Trials due to Worsening Symptoms Insufficient Treatment Response Rescue Medication Not Defined in the Protocol Defined in the Protocol Dropout Excluded from Analysis Treatment Bias Statistical Tradeoff Data Missing Issue Confounding Effect Missing Reduction Additional Variation Compromise Inference Power Issue To Discuss Rescue Medication Effect via a Psychiatric Clinical Trial 5/14/2015 SCT2015 2
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 133 with valid baseline 13 with no baseline 134 with valid baseline 123 completed study 10 discontinued study 124 completed study 10 discontinued study 32 rescue medication 26 rescue medication 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 5/14/2015 SCT2015 3
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 5/14/2015 SCT2015 4
Statistical Issues Confounding Effect Rescue Medication Treatment Outcome Testing Efficiency Tradeoff Rescue Dropout Power Rescue Variation Power 5/14/2015 SCT2015 5
Statistical Models Basic Model j T y j 1 i j i0 For a random intercepts model y u i 5/14/2015 SCT2015 6
Statistical Models Rescue Model y R u i v i 5/14/2015 SCT2015 7
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 5/14/2015 SCT2015 8
Impact of Rescue Medication on Treatment Effect 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 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 5/14/2015 SCT2015 9
Time to Rescue Medication Time to Rescue Medication as an Endpoint log-rank test: p = 0.2957 5/14/2015 SCT2015 10
Stratification Analysis 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 5/14/2015 SCT2015 11
Adjustment of Rescue Medication 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 5/14/2015 SCT2015 12
Sensitivity Analysis Rescue Med (Yes/No) Rescue Med on Weeks 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 LS Mean Difference Treatment Coefficient 5/14/2015 SCT2015 13
Simulations for Treatment Effect Confidence Intervals of Treatment Coefficients 5/14/2015 SCT2015 14
Testing Efficiency (Modeling and Simulations) Dropout and Rescue Model Let ( X, R ) be vector of (0, 1) variables: the indicator of the being a dropout X be a binary indicator of observing in the study (=1); th i patient receiving rescue medication (=1) in the R be th j visit to reduce the chance of P( X 1) 1 q j P ( X 0 X i( j 1) 1, R ) e R q j P ( X ) 0 X i( j 1 0, R ) 1 i 5/14/2015 SCT2015 15
Rescue medication effect on subject dropout ( ) Log-linear Model to Estimate Using the Trial Data Rescue Non-rescue Time 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) 5/14/2015 SCT2015 16
Role of in Dropout Reduction q j (%) 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 5/14/2015 SCT2015 17
Effect of Rescue Medication on Sample Size 5/14/2015 SCT2015 18
Effect of Rescue Medication on Variation 5/14/2015 SCT2015 19
Effect of Rescue Medication on Power 5/14/2015 SCT2015 20
Summary Rescue Medication To Avoid Inevitable Defined It in the Protocol Analysis Phase Design Phase Confounding Effect Test Efficiency Define Rescue Criteria Assess Rescue Impact Correlations Check Correlations No Correlations Additional Variation Power Assessment Rescue Threshold Simulations for Variation, Bias Stratified Analysis Adjusted in the Model Standard Analysis Sensitivity Analysis to Assess Rescue Effect Simulation to Assess Bias 5/14/2015 SCT2015 21
Society for Clinical Trials 36 th Annual Meeting Thank You 5/14/2015 SCT2015 22