Download - Experiences with a Novel Clinical Trial Designpeople.seas.harvard.edu/~samurphy/seminars/NCDEUAlmirall.pdf · 2The Methodology Center, Penn State University 3Psychiatry and Behavioral

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




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




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, ...





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.


DAlmiral

Rectangle




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!





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





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.


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



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.


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



Step Down: CBT Only R Maintain:

CBT



Responders R

Responders

Non-Responders R

O2 + Primary


Another Adaptive Intervention Within the SMART



Step Down: CBT Only

R Maintain:

CBT



Responders R

Responder

s

Non-Responders R

O2 + Primary


4 Embedded Adaptive Interventions in this SMART


CBT + MED Step Down: CBT Boost

Responders


CBT + MED Maintain:

CBT + MED Responders

Maintain: CBT Boost Responders

CBT Add Treatment:

CBT + MED Non-Responders


CBT Switch Treatment:

MED Non-Responders

AIS

1 AI

S 2

AIS

3 AI

S 4



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





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





SMART Design: Primary Aims

Choose a simple primary aim/question that aids developmentof an adaptive intervention.

Power the SMART to test this hypothesis.


Primary Aim Example 1What is the main effect of first-line treatment? End of study outcome (e.g., ANOVA).




CBT


Switch Treatmnt: MED

Responders R

Responders

Non-Responders R

O2 + Primary


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).




CBT


Switch Treatmnt: MED

Responders R

Responders

Non-Responders R

O2 + Primary


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.


CBT + MED Step Down: CBT Boost

Responders


CBT + MED Maintain:

CBT + MED Responders


CBT Add Treatment:

CBT + MED Non-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




SMART Design: Secondary Aims

Choose secondary aims/questions that further develop theAdaptive Intervention and take advantage of sequentialrandomization to eliminate confounding.





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


Non-Responders R

O2 + Primary

Tailoring Variable First-line Txt Second-line Txt Y

CBT


Secondary Aim Example 2Build a more deeply tailored adaptive intervention.



Step Down: CBT Only

R Maintain:

CBT



Responders R

Responders

Non-Responders R

O2 + Primary


O1 = demographics, genetics, sub-diagnoses, co-morbidities, etc…

O2 = adherence, time to NR, changes at home, etc…



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




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/


Extra Slides


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


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.


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.


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.


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.


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.


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
