Embed Size (px)
Citation preview
Sequenced Sequenced Treatment Treatment
Alternatives to Alternatives to Relieve Depression Relieve Depression
(STAR*D)(STAR*D)Stephen Wisniewski, PhDStephen Wisniewski, PhDEpidemiology Data CenterEpidemiology Data CenterSTAR*D Data Coordinating STAR*D Data Coordinating
CenterCenterUniversity of PittsburghUniversity of Pittsburgh
OutlineOutline
Overview of STAR*DOverview of STAR*D Introduction to the Equipoise-Introduction to the Equipoise-
Stratified Randomized DesignStratified Randomized Design Implementation of the Equipoise Implementation of the Equipoise
Stratified Randomized Design in Stratified Randomized Design in STAR*DSTAR*D
Overview of STAR*DOverview of STAR*D
OrganizationOrganization National Coordinating Center (Department of National Coordinating Center (Department of
Psychiatry, University of Texas Southwestern Psychiatry, University of Texas Southwestern Medical Center)Medical Center)
Data Coordinating Center (Epidemiology Data Data Coordinating Center (Epidemiology Data Center, University of Pittsburgh)Center, University of Pittsburgh)
14 Regional Centers14 Regional Centers 2-4 Clinical Sites2-4 Clinical Sites Primary Care and Specialty (Psychiatry)Primary Care and Specialty (Psychiatry)
Goal: Determine the best “next step” Goal: Determine the best “next step” treatments for those with treatment resistant treatments for those with treatment resistant depressiondepression
*Defined as nonremission
Obtain Consent
Level 2
Follow-upSatisfactory Response
Unsatisfactory Response*
CIT
Level 1Level 1
RandomizationRandomization Which treatments to Which treatments to
test as second-step test as second-step treatments?treatments? Efficacy studies have Efficacy studies have
identified a number of identified a number of different types of different types of treatments that were treatments that were effective in treating effective in treating depression.depression.
After much discussion, After much discussion, debate, arguing, etc., debate, arguing, etc., seven treatments were seven treatments were selected for the Level selected for the Level 2:2:
Level 2 Treatment Level 2 Treatment OptionsOptions VenlafaxinVenlafaxin SertralineSertraline BupropionBupropion Cognitive TherapyCognitive Therapy Citalopram + Cognitive Citalopram + Cognitive
TherapyTherapy Citalopram + Citalopram +
BupropionBupropion Citalopram + Citalopram +
BuspironeBuspirone
Randomize
SER BUP-SR
VEN-XR
CT CIT +BUP-SR
CIT +BUS
CIT +CT
Level 2Level 2
AugmentationOptions
SwitchOptions
Level 2ALevel 2A
RandomizeRandomize
BUP-BUP-SRSR
VEN-VEN-XRXR
Switch
Level 3Level 3
MRT NTP L-2 Tx +Li
L-2 Tx +
THYSwitch Augmentatio
n
Randomize
Level 4Level 4
TCP VEN-XR + MRT
Randomize
Switch
How do we How do we randomly assign a randomly assign a subject to one of subject to one of
the seven the seven treatments in Level treatments in Level
2?2?
Complete RandomizationComplete Randomization
Patient and clinician must be willing to Patient and clinician must be willing to accept all treatments offeredaccept all treatments offered Advantage: simple approachAdvantage: simple approach Disadvantage: Disadvantage:
Subjects and clinicians may have treatment Subjects and clinicians may have treatment preferences and would not be willing to be randomly preferences and would not be willing to be randomly assigned to a number of treatments. assigned to a number of treatments.
Because of this, those that are willing to accept all Because of this, those that are willing to accept all the treatment assignments do not represent a the treatment assignments do not represent a general population general population
Clinician’s ChoiceClinician’s Choice
Define broad classifications and let the Define broad classifications and let the clinician choose the treatment within the clinician choose the treatment within the class.class.
Patient and clinician must be willing to Patient and clinician must be willing to accept at least one treatment option within accept at least one treatment option within each classeach class
Advantages:Advantages: Clinician, in theory, knows something about the Clinician, in theory, knows something about the
patient so the choice of the treatment can be patient so the choice of the treatment can be optimizedoptimized
More generalizableMore generalizable
Clinician’s ChoiceClinician’s Choice
Disadvantages:Disadvantages: Because the assignment of treatment Because the assignment of treatment
options within a class are not randomly options within a class are not randomly assigned, the “best” treatment option assigned, the “best” treatment option within a class cannot be identifiedwithin a class cannot be identified
The Equipoise-Stratified The Equipoise-Stratified DesignDesign
Equipoise-Stratified (Lavori et al., Equipoise-Stratified (Lavori et al., 2000)2000) What is equipoise?What is equipoise?
To be in equipoise with respect to a set of To be in equipoise with respect to a set of prospective treatment options is to regard prospective treatment options is to regard them as approximately equal in terms of the them as approximately equal in terms of the likelihood of success.likelihood of success.
To consider a patient for entry into a To consider a patient for entry into a study, the clinician and patient must be in study, the clinician and patient must be in equipoise with respect to the treatment equipoise with respect to the treatment options.options.
Example Application of Example Application of ESRDESRD
Conducting a study to compare four Conducting a study to compare four treatments (TX1, TX2, TX3, TX4). treatments (TX1, TX2, TX3, TX4).
The treatment options can be The treatment options can be combined into two treatment combined into two treatment strategiesstrategies Strategy A (TX1, TX2)Strategy A (TX1, TX2) Strategy B (TX3, TX4)Strategy B (TX3, TX4)
This would create the following This would create the following acceptability strataacceptability strata
Example Application of Example Application of ESRD ESRD Acceptability of Acceptability of
Treatment OptionsTreatment Options
Acceptable Treatment OptionsAcceptable Treatment Options EligibleEligible
AcceptabilAcceptabilityity
Strategy AStrategy A Strategy BStrategy B ForFor
StratumStratum TX1TX1 TX2TX2 TX3TX3 TX4TX4 StudyStudy
11 YY YY YY YY YY
22 YY YY YY NN YY
33 YY YY NN YY YY
44 YY NN YY YY YY
55 NN YY YY NN YY
66 YY YY NN NN YY
77 YY NN NN YY YY
88 NN NN YY YY YY
Example Application of Example Application of ESRD ESRD Acceptability of Acceptability of
Treatment OptionsTreatment Options
Acceptable Treatment OptionsAcceptable Treatment Options EligibleEligible
AcceptabilAcceptabilityity
Strategy AStrategy A Strategy BStrategy B ForFor
StratumStratum TX1TX1 TX2TX2 TX3TX3 TX4TX4 StudyStudy
99 YY NN NN YY YY
1010 NN YY NN YY YY
1111 NN YY YY NN YY
1212 NN NN NN YY NN
1313 NN NN YY NN NN
1414 NN YY NN NN NN
1515 YY NN NN NN NN
1616 NN NN NN NN NN
Example Application of Example Application of ESRDESRD
For the equipoise-stratified design, For the equipoise-stratified design, subjects from acceptability strata 1 subjects from acceptability strata 1 through 11 are included in the studythrough 11 are included in the study
For the completely randomized For the completely randomized design, only those from acceptability design, only those from acceptability stratum 1 are included in the studystratum 1 are included in the study
For the clinician’s choice design, the For the clinician’s choice design, the comparison of treatments cannot be comparison of treatments cannot be made.made.
Example Application of Example Application of ESRDESRD
Want to do identify best treatmentWant to do identify best treatment Conduct all pairwise treatment Conduct all pairwise treatment
comparisonscomparisons TX1 vs. TX2, TX1 vs. TX3, TX1 vs. TX4, TX2 TX1 vs. TX2, TX1 vs. TX3, TX1 vs. TX4, TX2
vs. TX3, TX2 vs. TX4, TX3 vs. TX4vs. TX3, TX2 vs. TX4, TX3 vs. TX4 For a given comparison (e.g., TX1 vs. TX2), For a given comparison (e.g., TX1 vs. TX2),
compare rate out binary outcome across compare rate out binary outcome across two treatments, stratified by acceptability two treatments, stratified by acceptability stratum (Srata 1, 2, 3 and 6).stratum (Srata 1, 2, 3 and 6).
Use Mantel-Haenszel chi-square test to Use Mantel-Haenszel chi-square test to combine comparison across strata.combine comparison across strata.
Example Application of Example Application of ESRDESRD
Because conducting many pairwise Because conducting many pairwise tests, need to maintain the Type I tests, need to maintain the Type I error to be .05error to be .05
Use Bonferroni corrections, so each Use Bonferroni corrections, so each pairwise comparison is conducted at pairwise comparison is conducted at the .0083 (.05/6) level.the .0083 (.05/6) level.
The Equipoise-Stratified The Equipoise-Stratified DesignDesign
Equipoise-StratifiedEquipoise-Stratified AdvantagesAdvantages
GeneralizableGeneralizable Pairwise contrast can be built. For Pairwise contrast can be built. For
example, to compare A to B, can take example, to compare A to B, can take subjects that selected either the ABC strata subjects that selected either the ABC strata or the AB strata, and were randomly or the AB strata, and were randomly assigned to receive either treatment A or B.assigned to receive either treatment A or B.
Disadvantage: ComplicatedDisadvantage: Complicated
The Equipoise-Stratified The Equipoise-Stratified DesignDesign
In the second-step treatments of STAR*DIn the second-step treatments of STAR*D Patients/clinicians considered four strategiesPatients/clinicians considered four strategies
Medication switchMedication switch Medication augmentMedication augment Cognitive Therapy switchCognitive Therapy switch Cognitive Therapy augmentCognitive Therapy augment
Could exclude any of these, as long as multiple Could exclude any of these, as long as multiple treatments were still available.treatments were still available.
Exclude medication augment, cognitive therapy Exclude medication augment, cognitive therapy switch, cognitive therapy augment - OKswitch, cognitive therapy augment - OK
Exclude medication switch, medication augment, Exclude medication switch, medication augment, cognitive therapy switch – not OKcognitive therapy switch – not OK
ESRD in STAR*DESRD in STAR*D
Randomize
SER BUP-SR
VEN-XR
CT CIT +BUP-SR
CIT +BUS
CIT +CT
ESRD in STAR*D ESRD in STAR*D Study Design: Level 2Study Design: Level 2
AugmentationOptions
SwitchOptions
ESRD in STAR*DESRD in STAR*DLevel 2 ApproachLevel 2 Approach
Goal: Identify most effective 2Goal: Identify most effective 2ndnd step treatment step treatment Seven treatment options created too many strataSeven treatment options created too many strata Create acceptability stratum pooling strategiesCreate acceptability stratum pooling strategies
Must be willing to accept all medication switchesMust be willing to accept all medication switches Must be willing to accept all medication augmentsMust be willing to accept all medication augments
Creates four treatment strategy strataCreates four treatment strategy strata Medication SwitchMedication Switch Medication AugmentMedication Augment Cognitive Therapy SwitchCognitive Therapy Switch Cognitive Therapy AugmentCognitive Therapy Augment
ESRD in STAR*DESRD in STAR*DLevel 2 ApproachLevel 2 Approach
Analysis approach – step up procedureAnalysis approach – step up procedure Identify most effect medication switchIdentify most effect medication switch Identify most effect medication augmentIdentify most effect medication augment Identify most effective treatment strategyIdentify most effective treatment strategy
If a most effective medication switch or medication If a most effective medication switch or medication augment was identified, use those randomly augment was identified, use those randomly assigned to that specific medication in the assigned to that specific medication in the comparison across strategies.comparison across strategies.
If a most effective medication switch or medication If a most effective medication switch or medication augment was not identified, pool those randomly augment was not identified, pool those randomly assigned to any treatment that strategy for the assigned to any treatment that strategy for the comparison across strategies.comparison across strategies.
ESRD in STAR*D : ESRD in STAR*D : Level 2 Expected AcceptabilityLevel 2 Expected Acceptability
Acceptability of Treatment StrataAcceptability of Treatment Strata Enrolled in Level 2 of STAR*DEnrolled in Level 2 of STAR*D
Med AugMed Aug Med Med SwitchSwitch
CT AugCT Aug CT SwitchCT Switch PermittedPermitted Expected Expected %%
Yes Yes Yes Yes Yes 8
No Yes Yes Yes Yes < 1
Yes No Yes Yes Yes < 1
Yes Yes No Yes Yes 1
Yes Yes Yes No Yes 1
No No Yes Yes Yes 11
No Yes No Yes Yes 12
No Yes Yes No Yes 0
Yes No No Yes Yes 0
Yes No Yes No Yes 12
Yes Yes No No Yes 25
Yes No No No Yes 14
No Yes No No Yes 14
No No Yes No No -
No No No Yes No -
ESRD in STAR*D : ESRD in STAR*D : Level 2 Observed & Expected Level 2 Observed & Expected
AcceptabilityAcceptabilityAcceptability of Treatment StrataAcceptability of Treatment Strata Enrolled in Level 2 of STAR*DEnrolled in Level 2 of STAR*D
Med AugMed Aug Med Med SwitchSwitch
CT AugCT Aug CT SwitchCT Switch PermittedPermitted Expected Expected %%
Observed Observed %%
Yes Yes Yes Yes Yes 8 1
No Yes Yes Yes Yes < 1 < 1
Yes No Yes Yes Yes < 1 < 1
Yes Yes No Yes Yes 1 0
Yes Yes Yes No Yes 1 2
No No Yes Yes Yes 11 3
No Yes No Yes Yes 12 7
No Yes Yes No Yes 0 < 1
Yes No No Yes Yes 0 < 1
Yes No Yes No Yes 12 11
Yes Yes No No Yes 25 4
Yes No No No Yes 14 30
No Yes No No Yes 14 41
No No Yes No No - -
No No No Yes No - -
ESRD in STAR*DESRD in STAR*D
Any treatment: 1.5% (21/1,438 )Any treatment: 1.5% (21/1,438 ) Cognitive Therapy: 25.6% Cognitive Therapy: 25.6%
(368/1,438)(368/1,438) Medication Switch: 55.8% Medication Switch: 55.8%
(803/1,438)(803/1,438) Medication Augment: 48.4 Medication Augment: 48.4
(696/1,438)(696/1,438)
