experiences with a novel clinical trial...
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Experiences with a Novel Clinical Trial DesignDeveloping Dynamic, Sequential Treatments that Optimize Mental Health Outcomes
Introduction to Adaptive Interventions and SMART Designs2:45-3:10PM, Daniel Almirall and Susan Murphy, UMich
SMART Studies for Alcohol and Cocaine Dependence3:15-3:40PM, James McKay, UPenn
Adaptive Treatments for Children with ADHD3:45-4:10PM, William E. Pelham, FIU
Testing Variants of Treatments for Substance UseDisorders During Pregnancy
4:30-4:55PM, Hendree Jones, RTI
Innovative Communication Intervention for OlderNonverbal Children with Autism
5:00-5:25PM, Connie Kasari, UCLA
Introduction to Adaptive Interventions andSMART Study Design Principles
Daniel Almirall1,2 Scott N Compton3
Susan A Murphy1,2,4
1Institute for Social Research, University of Michigan2The Methodology Center, Penn State University
3Psychiatry and Behavioral Sciences, Duke University Medical Center4Department of Statistics, University of Michigan
Developing Dynamic, Sequential Treatments that OptimizeMental Health Outcomes, NCDEU, Boca Raton, Florida
June 14, 2011No conflicts of interest to report.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
Disclosures or Conflicts of Interest: None
Disclosures or Conflicts of Interest
None
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
Outline
Adaptive InterventionsWhat? Why?Adaptive Intervention Development Considerations
Sequential Multiple Assignment Randomized Trial (SMART)What are SMARTs?
SMART Design PrinciplesKeep it SimpleChoosing Primary and Secondary Hypotheses
Discussion
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
What? Why?Adaptive Intervention Development Considerations
Definition of an Adaptive Intervention
An adaptive intervention (AI) is a sequence of individuallytailored decision rules that specify whether, how, and when toalter the intensity, type, dosage, or delivery of treatment atcritical decision points in the medical care process.
Adaptive Interventions operationalize sequential decisionmaking with the aim of improving clinical practice.
aka: dynamic treatment regimes, adaptive treatment strategies, treatmentalgorithms, structured treatment interruptions, ...
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
What? Why?Adaptive Intervention Development Considerations
Concrete Example of Adaptive InterventionPediatric Anxiety Example (SAD, GAD, SoP)
Maintain: CBT
CBT
Add Treatment: CBT + MED
Responder
s
Non-Responders
Tailoring Variable First-line Txt Second-line Txt
I Goal is to minimize the child’s symptom profile/trajectory.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
What? Why?Adaptive Intervention Development Considerations
Why Adaptive Interventions?Necessary because...
I The chronic nature of mental health disorders
I Waxing and waning course (multiple relapse, recurrence)I Genetic and non-genetic factors influence courseI Co-occuring disorders may arise
I High patient heterogeneity in response to treatment
I Within person (over time) differential response to treatmentI Between person differential response to treatment
I More is not always better!
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
What? Why?Adaptive Intervention Development Considerations
Why Adaptive Interventions?Can be used to inform how to best...
I Adapt treatment to a patient’s chronic/changing courseI Deliver appropriate treatment when needed mostI React to non-adherence or side-effect profilesI Reduce treatment burden; only what is necessaryI Deliver early treatments with positive downstream effectsI Sift through available treatment options
I ⇒ More personalized care, over timeI ⇒ Improving clinical practice
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
What? Why?Adaptive Intervention Development Considerations
Why Adaptive Interventions?Can be used to inform how to best...
I Adapt treatment to a patient’s chronic/changing courseI Deliver appropriate treatment when needed mostI React to non-adherence or side-effect profilesI Reduce treatment burden; only what is necessaryI Deliver early treatments with positive downstream effectsI Sift through available treatment options
I ⇒ More personalized care, over timeI ⇒ Improving clinical practice
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
What? Why?Adaptive Intervention Development Considerations
Developing an Adaptive InterventionI For who are we developing the adaptive strategy?
Population, or Context, question.
I What is the goal of the adaptive intervention?Objectives question.
I What is the optimal sequencing of treatments?Sequencing question.
I When do we switch, augment, or maintain treatment?Timing question.
I Based on what information do we make decisions?Tailoring question.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
What is a tailoring variable?A time-varying measure that prescribes one treatment at one level and anothertreatment at another level.
Mea
n A
nxi
ety
Sco
re
Adherence to medication relative to CBT
Among responders to combination CBT + MED:
More adherence to CBT More adherence to MED
Step Down to CBT Only
Maintain CBT+MED
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
What are SMARTs?
What is a Sequential Multiple AssignmentRandomized Trial (SMART)?
I Multi-stage trials; same participants throughoutI Each stage corresponds to a critical decision pointI At each stage, subjects are randomized to a set of
treatment optionsI Treatment options at randomization may be restricted
depending on intermediate outcome/treatment history
I The goal of a SMART is to inform the development ofadaptive intervention strategies.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
What are SMARTs?
What is a Sequential Multiple AssignmentRandomized Trial (SMART)?
I Multi-stage trials; same participants throughoutI Each stage corresponds to a critical decision pointI At each stage, subjects are randomized to a set of
treatment optionsI Treatment options at randomization may be restricted
depending on intermediate outcome/treatment history
I The goal of a SMART is to inform the development ofadaptive intervention strategies.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Concrete Example of a SMART: Pediatric Anxiety
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Maintain: CBT + MED
Step Down: CBT Only
R Maintain:
CBT
CBT Add Treatment: CBT + MED
Switch Treatment: MED
Responders R
Responders
Non-Responders R
O2 + Primary
Tailoring Variable First-line Txt Second-line Txt Y O1
One Adaptive Intervention Within the SMART
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Maintain: CBT + MED
Step Down: CBT Only R Maintain:
CBT
CBT Add Treatment: CBT + MED
Switch Treatment: MED
Responders R
Responders
Non-Responders R
O2 + Primary
Tailoring Variable First-line Txt Second-line Txt Y O1
Another Adaptive Intervention Within the SMART
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Maintain: CBT + MED
Step Down: CBT Only
R Maintain:
CBT
CBT Add Treatment: CBT + MED
Switch Treatment: MED
Responders R
Responder
s
Non-Responders R
O2 + Primary
Tailoring Variable First-line Txt Second-line Txt Y O1
4 Embedded Adaptive Interventions in this SMART
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Step Down: CBT Boost
Responders
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Maintain:
CBT + MED Responders
Maintain: CBT Boost Responders
CBT Add Treatment:
CBT + MED Non-Responders
Maintain: CBT Boost Responders
CBT Switch Treatment:
MED Non-Responders
AIS
1 AI
S 2
AIS
3 AI
S 4
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
Keep it SimpleChoosing Primary and Secondary Hypotheses
SMART Design Principles
I KISS Principle: Keep It Simple, Straightforward
I Power for Simple Important Primary Hypotheses
I Take Appropriate Steps to Develop an Optimal AdaptiveIntervention
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
Keep it SimpleChoosing Primary and Secondary Hypotheses
Keep It Simple, StraightforwardOverarching Principle
At each stage, or critical decision point,...I Restrict class of treatment options by ethical, feasibility, or
strong scientific considerations
I Use low dimensional summary to restrict subsequenttreatments
I Use binary responder statusI Should be easy to use in actual clinical practice
I Collect additional, auxiliary time-varying measuresI To develop a more deeply-tailored Adaptive InterventionI Think time-varying effect moderators
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
Keep it SimpleChoosing Primary and Secondary Hypotheses
SMART Design: Primary Aims
Choose a simple primary aim/question that aids developmentof an adaptive intervention.
Power the SMART to test this hypothesis.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Primary Aim Example 1What is the main effect of first-line treatment? End of study outcome (e.g., ANOVA).
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Maintain: CBT + MED
Step Down: CBT Only R Maintain:
CBT
CBT Add Treatment: CBT + MED
Switch Treatmnt: MED
Responders R
Responders
Non-Responders R
O2 + Primary
Tailoring Variable First-line Txt Second-line Txt Y O1
PowerES N0.8 520.5 1280.2 788α = 0.05β = 0.20
Primary Aim Example 1What is the main effect of first-line treatment? Longitudinal outcome (e.g., LMM).
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Maintain: CBT + MED
Step Down: CBT Only R Maintain:
CBT
CBT Add Treatment: CBT + MED
Switch Treatmnt: MED
Responders R
Responders
Non-Responders R
O2 + Primary
Tailoring Variable First-line Txt Second-line Txt Y O1
PowerES N0.8 340.5 830.2 505ρ = 0.60α = 0.05β = 0.20
Primary Aim Example 2Identify the best of the 4 embedded adaptive intervention strategies.
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Step Down: CBT Boost
Responders
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Maintain:
CBT + MED Responders
Maintain: CBT Boost Responders
CBT Add Treatment:
CBT + MED Non-Responders
Maintain: CBT Boost Responders
CBT Switch Treatment:
MED Non-Responders
AIS
1 AI
S 2
AIS
3 AI
S 4
ES N0.5 730.3 208π = 0.85
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
Keep it SimpleChoosing Primary and Secondary Hypotheses
SMART Design: Secondary Aims
Choose secondary aims/questions that further develop theAdaptive Intervention and take advantage of sequentialrandomization to eliminate confounding.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
Keep it SimpleChoosing Primary and Secondary Hypotheses
Secondary Aim Example 1Second-line treatment tailoring aim.
O2 = CBT adherence, time to non-response, allegiance with therapist, changes in home environment
Add Treatment: CBT + MED
Switch Treatment: MED
Non-Responders R
O2 + Primary
Tailoring Variable First-line Txt Second-line Txt Y
CBT
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Secondary Aim Example 2Build a more deeply tailored adaptive intervention.
Add Treatment: CBT + MED + FT Non-Responders
CBT + MED Maintain: CBT + MED
Step Down: CBT Only
R Maintain:
CBT
CBT Add Treatment: CBT + MED
Switch Treatment: MED
Responders R
Responders
Non-Responders R
O2 + Primary
Tailoring Variable First-line Txt Second-line Txt Y O1
O1 = demographics, genetics, sub-diagnoses, co-morbidities, etc…
O2 = adherence, time to NR, changes at home, etc…
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
Messages and Misconceptions
I Adaptive Intervention? vs SMART? vs Adaptive Trial?I “Adaptive Trial” has other meanings in trials literatureI In SMART, same patients participate in multiple stages
I SMARTs do not necessarily require larger sample sizes
I SMARTs can be seen as developmental trialsI Next trial will compare the SMART-optimized Adaptive
Intervention versus usual care or other state-of-the-arttreatment
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive InterventionsSequential Multiple Assignment Randomized Trial (SMART)
SMART Design PrinciplesDiscussion
Thank you! Questions?
Email me with questions about this presentation:I [email protected]
These slides will be posted on my website:I http://www-personal.umich.edu/∼dalmiral/
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Extra Slides
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Adaptive Treatment for Children with ADHDB. Pelham, Florida International University
Continue Medication Responders
Medication Increase Medication Dose
Add Behavioral Intervention
R Continue
Behavioral Intervention Behavioral
Intervention Increase Behavioral
Intervention
Add Medication
Non-Responders R
Responders
Non-Responders R
Treatment for Alcohol DependenceD. Oslin, University of Pennsylvania
Early Trigger for NR: 2+ HDD CBI
CBI + Naltrexone
R
Late Trigger for NR: 5+ HDD
CBI
CBI + Naltrexone
Non-Response R
Non-Response R
Naltrexone
TDM + Naltrexone
8 Week Response R
Naltrexone
TDM + Naltrexone
8 Week Response R
Other Alternatives
I Piecing Together Results from Multiple TrialsI Choose best first-line treatment on the basis of a two-arm
RCT; then choose best second-line treatment on the basisof another separate, two-arm RCT
I Concerns: delayed therapeutic effects, and cohort effects
I Observational (Non-experimental) Comparisons of AIsI Using data from longitudinal randomized trialsI May yield results that inform a SMART proposalI Understand current treatment sequencing practicesI Typical problems associated with observational studies
I Expert Opinion
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Why Not Use Multiple Trials to Construct an AIThree Concerns about Using Multiple Trials as an Alternative to a SMART
1. Concern 1: Delayed Therapeutic Effect
2. Concern 2: Diagnostic Effects
3. Concern 3: Cohort Effects
All three concerns emanate from the basic idea thatconstructing an adaptive intervention based on a myopic, local,study-to-study point of view may not be optimal.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Why Not Use Multiple Trials to Construct an AIConcern 1: Delayed Therapeutic Effects, or Sequential Treatment Interactions
Positive Synergy Btwn First- and Second-line Treatments
Tapering off medication after 12 weeks of use may not appearbest initially, but may have enhanced long term effectivenesswhen followed by a particular augmentation, switch, ormaintenance strategy.
Tapering off medication after 12 weeks may set the child up forbetter success with any one of the second-line treatments.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Why Not Use Multiple Trials to Construct an AIConcern 1: Delayed Therapeutic Effects, or Sequential Treatment Interactions
Negative Synergy Btwn First- and Second-line Treatments
Keeping the child on medication an additional 12 weeks mayproduce a higher proportion of responders at first, but may alsoresult in side effects that reduce the variety of subsequenttreatments available if s/he relapses.
The burden associated with continuing medication an additional12 weeks may be so high that non-responders will not adhereto second-line treatments.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Why Not Use Multiple Trials to Construct an AIConcern 2: Diagnostic Effects
Tapering off medication after 12 weeks initial use may notproduce a higher proportion of responders at first, but may elicitsymptoms that allow you to better match subsequent treatmentto the child.
The improved matching (personalizing) on subsequenttreatments may result in a better response overall as comparedto any sequence of treatments that offered an additional 12weeks of medication after the initial 12 weeks.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
Why Not Use Multiple Trials to Construct an AIConcern 3: Cohort Effects
I Children enrolled in the initial and secondary trials may bedifferent.
I Children who remain in the trial(s) may be different.I Characteristics of adherent children may differ from study
to study.I Children that know they are undergoing adaptive
intervention strategies may have different adherencepatterns.
Bottom line: The population of children we are makinginferences about may simply be different from study-to-study.
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions
SMART Design PrinciplesChoose a Longitudinal Response Measure
Why choose a longitudinal outcome, or a with-in personsummary of outcomes over time?
I These are chronic disorders (e.g., child-hood onset anxietydisorder)
I Outcome should incorporate time to initial response as acomponent
I Quick initial relief of symptoms should be valued
Almirall, Compton, Murphy Experimental Designs for Developing Adaptive Interventions