NIMH Practical Trials: Implications for

Practice and Policy

Matthew V. Rudorfer, M.D.Division of Services & Intervention Research

National Institute of Mental Health

June 5, 2007

Two Kinds of Two Kinds of Translational ResearchTranslational Research

BenchBench BedsideBedside

PathophysiologyDiagnostic tests

BiomarkersNew treatments

PracticePractice

Practical TrialsClinical Trials Networks

Services ResearchDissemination & Implementation

Utility of Large Studies –“Practical Clinical Trials”

• Public health perspective on clinical issues– Big questions and community effect– Chronic diseases require long term look

• Longitudinal follow-up and link intermediate change to long term outcomes

• Linkage of biological (biomarker, genetics – Perlis et al, STAR*D, Arch Gen Psychiatry June 2007) and clinical data; potential for targeted interventions

• Identification of subgroups (differential response -- “personalized treatment”)

Personalized Treatment

Optimizing the Benefit:Risk Ratio

Practical Clinical Trials: NIMH Approach

• 1999 – 2006: Multiple large clinical trials launched under contract mechanism

• 2006 – onward: With completion of practical trials, infrastructure for disorder-focused clinical trials networks formed from nucleus of high-performing sites + coordinating center

Clinical Trial DesignEfficacy Effectiveness

Patients Narrow dx; few comorbidities or concurrent meds

Few exclusion criteria

Phase II, III III, IV

N 10s – 100s 100s – 1,000s

Settings Health care Various

Masked Treatment

Yes (Protocol) No (Clinician / Algorithm)

Masked Raters Yes Yes

OutcomeMeasures

Symptomatic only Functional, Cost/ Utilization as well

Methodology Designed for High Generalizability in Practical Trials

• Equipoise design, in some cases using patient preference, reflects practice, increasing generalizability of findings

• Real-world patients enrolled (comorbidities OK)• Use of cutting-edge technology, e.g. Web-based quality

control of treatment, ratings entry via IVR• Advances in valid and reliable clinical ratings, e.g. QIDS-

C or QIDS-SR instead of traditional Hamilton score; “all-cause discontinuation” as a measure of effectiveness

• Outcomes beyond symptomatic ratings, e.g. quality of life, functional measures

NIMH Contracts: Practical Clinical Trials

• STEP-BD (Bipolar Disorder)– 4,360 / 13 sites– Standard care and random pathways

• CATIE (Schizophrenia / Alzheimer’s Disease)– 1,914 / 57 sites– 1,493 in Schizophrenia; 421 in Alzheimer’s Disease– Randomized comparison

• STAR*D (Refractory Depression)– 4,041 / 41 sites– Sequential pathways

Less than 1/3 of symptomatic bipolar patients reach recovery and remain well over 2 years in STEP-BD

• Achieved recovery 58.5% – (< 2 mood symptoms for at least 8 weeks)

• Relapse into depression 34.7% • Relapse into mood elevation 13.8%• Total relapse rate 48.5%• Total that stayed recovered over 2 years (100%-48.5%) 51.5%

• Total who recovered and remained free of depressive and mood elevation recurrences over 2 years(51.5% out of 58.5% who achieved remission)

30.1%

Perlis et al, STEP-BD, Am J Psychiatry 2006 Feb;163:217-24.

N=1469 who entered symptomatic

Anxiety comorbid conditions with higher risk of relapse in bipolar disorder in STEP-BD

Otto et al., STEP-BD, Br J Psychiatry 2006 Jul;189:20-5.

N=489Overall relapse rate = 41.4%

Overall Hazard Ratio (HR)= 1.764( 2=10.9, P=0.001)

HR=1.55 for one disorder HR=2.17 for two or more disorders HR=2.07 for social anxiety disorder HR=2.45 for PTSD

without anxiety

with anxiety

April 26, 2007

         Effectiveness of Adjunctive Antidepressant Treatment

for Bipolar Depression

Gary S. Sachs, M.D., Andrew A. Nierenberg, M.D., Joseph R. Calabrese, M.D., Lauren B. Marangell, M.D., Stephen R. Wisniewski, Ph.D., Laszlo Gyulai, M.D., Edward S. Friedman, M.D., Charles L. Bowden, M.D., Mark D. Fossey, M.D., Michael J. Ostacher, M.D., M.P.H., Terence A. Ketter, M.D., Jayendra Patel, M.D., Peter Hauser, M.D., Daniel Rapport, M.D., James M. Martinez, M.D., Michael H. Allen, M.D., David J. Miklowitz, Ph.D., Michael W. Otto, Ph.D., Ellen B. Dennehy, Ph.D., and Michael E. Thase, M.D.

Intensive psychosocial interventions for bipolar depression better than collaborative care, but over

a third never reach recovery

Miklowitz et al., STEP-BD, Arch Gen Psychiatry, April 2007

0

10

20

30

40

50

60

70

80

1 2 3 4 5 6 7 8 9 10 11 12Month

% Well

Intensive Treatment

Collaborative Care

1-year recovery rate for intensive group, 105/163 [64.4%]; for CC, 67/130 [51.5%]; log-rank 2(1) = 6.20, p = 0.013; hazard ratio (HR) = 1.47; 95% CI = 1.08-2.00

Am J Psychiatry 164:201-204, February 2007© 2007 American Psychiatric Association

Special Article

STAR*D: What Have We Learned? A. John Rush, M.D.

STAR*D represents a 7-year effort by literally hundreds of people and thousands of patients. Future reports will 1) compare longer-term outcomes of the various randomized treatments (e.g., does cognitive therapy prevent relapse better than medication as either a switch or augmentation strategy?); 2) identify which patients benefit from which treatments (e.g., do different patients [defined by different clinical features or genetic polymorphisms] respond differently to different treatments?); and 3) determine whether different treatment sequences (in steps 1 to 4) are preferred for some but not other patients.

Volume 353:1209-1223 September 22, 2005 Number 12

Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia

Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., et al. for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators

CATIE:CATIE:Primary Questions Addressed Primary Questions Addressed

• How do the atypical antipsychotic medications compare with an older, less expensive conventional antipsychotic?

• How do the atypical antipsychotics compare to one another?

• Are the atypical antipsychotics cost-effective?

Stroup TS et al. Schizophr Bull. 2003;29:15-31.

Use of Atypical Antipsychotic Medications in U.SUse of Atypical Antipsychotic Medications in U.S..

0

10,000

20,000

30,000

40,000

50,000

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Conventionals Clozaril Risperdal Zyprexa Seroquel Geodon Abilify

Source: IMS NPA Plus, Dec 05. Lieberman – Presentation to NIMH Advisory Council, Sept 2006

TRx (000s)

1500 participants with schizo-

phrenia

CLOZAPINE(open-label)

OLANZAPINE, QUETIAPINE or RISPERIDONE

OLANZAPINE, QUETIAPINE or RISPERIDONE

ZIPRASIDONE

Participants who discontinue Phase 1 choose either the

clozapine or the ziprasidone randomization pathways

R

OLANZAPINE

QUETIAPINE

RISPERIDONE

ZIPRASIDONE

PERPHENAZINE

Participants who discontinue Phase 2 choose one of the

following open-label treatments

•ARIPIPRAZOLE•CLOZAPINE

•FLUPHENAZINE DECANOATE

•PERPHENAZINE

•RISPERIDONE

•OLANZAPINE

•ZIPRASIDONE

•QUETIAPINE

•2 of the antipsychotics above

Phase 1* Phase 2 Phase 3

R

R

Responders stay on assigned medication for duration of 18-month treatment period

* Phase 1A: participants with tardive dyskinesia do not get randomized to perphenazinePhase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or

risperidone) before they are eligible for Phase 2

Double-blind, random treatment assignment.

CATIE Schizophrenia Trial Design

No one assigned to same drug as in Phase 1

Stroup et al 2003

0

0.2

0.4

0.6

0.8

1

0 3 6 9 12 15 18

Olanzapine (n=330)

Perphenazine (n=257)

Quetiapine (n=329)

Risperidone (n=333)

Ziprasidone (n=183)

Pro

po

rtio

n o

f P

atie

nts

with

ou

t E

ven

t

Time to Discontinuation for Any Cause (mo)

PHASE 1: Time to Discontinuation for Any PHASE 1: Time to Discontinuation for Any ReasonReason

36%

26% 25%21 %18%

▬▬▬ Risperidone (n=333) ▬▬▬ Perphenazine (n=257)

▬▬▬ Ziprasidone (n=183) ▬▬▬ Quetiapine (n=329)

▬▬▬ Olanzapine (n=330)

-15.0

-10.0

-5.0

0.0

5.0

10.0

15.0

20.0

Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone

0%

5%

10%

15%

Prolactin: Change from Baseline

Problems with Movement During the TrialEx

posu

re-a

djus

ted

Mea

n(n

g/m

L)Pe

rcen

t (%

)

Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone

Wei

ght G

ain

>7%

Expo

sure

-adj

uste

d M

ean

(mg/

dL)

0%

10%

20%

30%

40%Body Weight: Change from Baseline

Fasting Glucose: Change from Baseline

Fasting Triglycerides: Change from Baseline

0.0

5.0

10.0

15.0

-20.0

-5.0

10.0

25.0

40.0

Expo

sure

-adj

uste

d M

ean

(mg/

dL)

OlanzapineQuetiapineRisperidonePerphenazine Ziprasidone

OlanzapineQuetiapineRisperidonePerphenazine Ziprasidone

OlanzapineQuetiapineRisperidonePerphenazine Ziprasidone

American Journal of Psychiatry 163:600-610, April 2006

Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior Atypical Antipsychotic Treatment

Joseph P. McEvoy, M.D., Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Sonia M. Davis, Dr.P.H., Herbert Y. Meltzer, M.D., Robert A. Rosenheck, M.D., Marvin S. Swartz, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Clarence E. Davis, Ph.D., Joanne Severe, M.S., John K. Hsiao, M.D. for the CATIE Investigators

CATIE Phase 2: CATIE Phase 2: Preference Pathways Preference Pathways

(for people who discontinue Phase 1)(for people who discontinue Phase 1)

EfficacyPathway

TolerabilityPathway

Clozapine—open-label

Olanzapine, Quetiapine, or Risperidone—drug not taken in Phase 1

Ziprasidone

Randomized

Randomized

Stroup TS et al. Schizophr Bull. 2003;29:15-31.

PHASE 2E: Time to Discontinuation PHASE 2E: Time to Discontinuation for Any Reasonfor Any Reason

0

0.2

0.4

0.6

0.8

1

0 3 6 9 12 15 18

Clozapine (N=45)Olanzapine (N=17)

Quetiapine (N=14)Risperidone (N=14)

Pro

po

rtio

n o

f P

atie

nts

with

ou

t E

ven

t

Time to Discontinuation for Any Cause (mo)

29%44%

14%7%

PHASE 2T:PHASE 2T: Time to Discontinuation Time to Discontinuation for Any Reasonfor Any Reason

0

0.2

0.4

0.6

0.8

1

0 4 8 12 16

OlanzapineQuetiapine

RisperidoneZiprasidone

Pro

po

rtio

n o

f P

atie

nts

with

out E

vent

Time to Discontinuation for Any Cause (mo)

33%

23%

36%

16%

Negative Symptoms and Negative Symptoms and Cognitive FunctionCognitive Function

•No differences between atypical antipsychotics and a conventional antipsychotic (perphenazine) on negative symptoms and cognitive functions

December 1, 2006

Older Medication May Be More Cost-Effective for Some Patients with Schizophrenia

A new study analyzing the economic implications of CATIE concludes that the older (first generation) antipsychotic medication perphenazine was less expensive and no less effective than the newer (second generation) medications used in the trial during initial treatment, suggesting that older antipsychotics still have a role in treating schizophrenia. Total monthly health costs, a figure that includes both average medication costs and inpatient and outpatient costs, were up to 30 percent lower for those taking perphenazine than for those taking the second generation medications.

-- NIMH Press Release Re: Rosenheck et al, Am J Psychiatry, December 2006

Study May Boost Use of Cheaper Antipsychotic Drug

By Avery Johnson, The Wall Street Journal,December 1, 2006 For the cost-effectiveness portion of the Catie study, a team of researchers led by Yale Medical School's Robert Rosenheck found that patients taking the generic antipsychotic paid $960 in average health costs per month, including the $50 price of the drug. The average monthly cost of treatment with Eli Lilly & Co.'s Zyprexa, for instance, was $1,404 -- the lowest of the branded drugs -- after accounting for the $545 per month cost of the antipsychotic, plus additional medications and hospital costs. Average health costs for patients on Johnson & Johnson's Risperdal were $1,533 a month, including $474 for the drug. Two other branded drugs were also analyzed

                                                                                     

                                                                                       

CATIE HIGHLIGHTSCATIE HIGHLIGHTS– All antipsychotic medications studied are

effective but have substantial limitations reflected by high discontinuation rates

– Olanzapine and Clozapine show the best efficacy but the worst side effects

– Perphenazine was surprisingly comparable to atypicals

– Differences in types and severity of side effects

– Ziprasidone has least weight and metabolic side effects (Aripiprazole was released later)

“CATIE has opened the door to more choice in treatment options."

-- Robert Rosenheck, M.D.

Treatments for persons with schizophrenia must be individualized. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects and past treatment history in choosing an appropriate medication.

Lieberman – Presentation to NIMH Advisory Council, Sept 2006

Issues in Schizophrenia Treatment Research Still Needing Attention

• Need for strategies beyond clozapine or alternatives to clozapine for patients with refractory symptoms

• Rational antipsychotic polypharmacy? • What are optimal strategies for first-episode psychosis?• How to enhance treatment adherence ?

Lieberman – Presentation to NIMH Advisory Council, Sept 2006

355:1525-1538 October 12, 2006 Number 15

Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's Disease

Lon S. Schneider, M.D., Pierre N. Tariot, M.D., Karen S. Dagerman, M.S., Sonia M. Davis, Dr.P.H., John K. Hsiao, M.D., M. Saleem Ismail, M.D., Barry D. Lebowitz, Ph.D., Constantine G. Lyketsos, M.D., M.H.S., J. Michael Ryan, M.D., T. Scott Stroup, M.D., David L. Sultzer, M.D., Daniel Weintraub, M.D., Jeffrey A. Lieberman, M.D., for the CATIE-AD Study Group

Schneider et al, CATIE-AD, N Engl J Med, Oct 2006

"The antipsychotic medications may be effective against some symptoms in Alzheimer's patients compared to placebo, but their tendency to cause intolerable adverse side effects in this vulnerable population offsets their benefits."

Lon Schneider, MD

Psychotherapy in NIMH Effectiveness Trials – completed

• STEP-BD (Bipolar Depression) – 3 types of structured psychotherapy are effective adjuncts to pharmacotherapy (Miklowitz et al, Arch Gen Psychiatry, April 2007)

• STAR*D (Refractory Depression)

– Only 26% of patients agreed to treatment with cognitive therapy (CT) as a second-line treatment after inadequate response to citalopram. Responses to CT, as monotherapy or augmenting citalopram, were equivalent to medication-only groups. Time to remission was slower with CT but with fewer side effects(Thase et al, & Wisniewski et al, Am J Psychiatry, May 2007)

Psychotherapy in NIMH Effectiveness Trials – in progress

• Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP / Chronic Major Depression) – Does CBASP or supportive psychotherapy add to

pharmacotherapy in the treatment of chronic forms of major depression? (Kocsis et al)

• Coordinated Anxiety Learning and Management (CALM / Anxiety Disorders) – Does computer-based individualized CBT add to

pharmacotherapy for anxiety disorders in primary care? (Roy-Byrne et al)

What Questions Should Be Pursued Next?• Widely used treatments and treatment

combinations that are untested?• New molecules ready for wider testing?• Patient attrition?• Longer-term outcomes?• Tailoring treatment to individuals?• Enhancing cost efficiency?• Practice procedures that are controlled by payor

costs without regard to patient outcomes?

Rush – Presentation to NIMH Advisory Council, Sept 2006

What’s Next at NIMH

• Three new clinical trials networks (Depression, Bipolar Disorder, Schizophrenia), building upon completed Practical Clinical Trials

• Platform funding• Central data management• Collaboration with new partners• Identify challenging public mental health

questions suitable for study on Networks• Continue regular grant support of non-Network

services and interventions research

www.nimh.nih.gov/ncdeu/index.cfm

For complete details of NIMH-supported Clinical Trials, please see http://www.nimh.nih.gov/studies/index.cfm