the national institute of mental health clinical antipsychotic trials

The National Institute of Mental HealthClinical Antipsychotic Trials of Intervention

Effectiveness (CATIE) Project: SchizophreniaTrial Design and Protocol Development

by T. Scott Stroup, Joseph P . McEvoy, Marvin S. Swartz, Matthew J. Byerly,Ira D. Qlick, Jose M. Canive, Mark F. McQee, Qeorge M. Simpson,

Michael C. Stevens, and Jeffrey A. Lieberman*

Abstract

The National Institute of Mental Health initiated theClinical Antipsychotic Trials of InterventionEffectiveness (CATIE) program to evaluate the effec-tiveness of antipsychotic drugs in typical settings andpopulations so that the study results will be maximallyuseful in routine clinical situations. The CATIE schizo-phrenia trial blends features of efficacy studies andlarge, simple trials to create a pragmatic trial that willprovide extensive information about antipsychoticdrug effectiveness over at least 18 months.

The protocol allows for subjects who receive astudy drug that is not effective to receive subsequenttreatments within the context of the study. Medicationdosages are adjusted within a defined range accordingto clinical judgment The primary outcome is all-causetreatment discontinuation because it represents animportant clinical endpoint that reflects both clinicianand patient judgments about efficacy and tolerability.Secondary outcomes include symptoms, side effects,neurocognitive functioning, and cost-effectiveness.

Approximately 50 clinical sites across the UnitedStates are seeking to enroll a total of 1,500 personswith schizophrenia. Phase 1 is a double-blinded ran-domized clinical trial comparing treatment with thesecond generation antipsychotics olanzapine, quetia-pine, risperidone, and ziprasidone to perphenazine, amidpotency first generation antipsychotic If the ini-tially assigned medication is not effective, subjects maychoose one of the following phase 2 trials: (1) random-ization to open-label clozapine or a double-blindedsecond generation drug that was available but notassigned hi phase 1; or (2) double-blinded randomiza-tion to ziprasidone or another second generation drugthat was available but not assigned in phase 1. If thephase 2 study drug is discontinued, subjects may enter

phase 3, in which clinicians help subjects select anopen-label treatment based on individuals' experiencesin phases 1 and 2.

Keywords: Randomized clinical trial, schizophre-nia, antipsychotic drugs, effectiveness, longitudinal.

Schizophrenia Bulletin, 29(1):15-31,2003.

The advent of the newer atypical or second generationantipsychotic medications developed in the wake of cloza-pine (olanzapine, quetiapine, risperidone, and ziprasidone)has raised considerable hope that treatments for schizo-phrenia will be more effective and better tolerated than inthe past. The use of atypical medications has steadilygrown, and this trend is expected to continue. However,there is no definitive evidence that these expensive med-ications can reduce morbidity and hospital use andimprove community functioning, as compared to the con-ventional or first generation antipsychotic drugs.

The existing evidence regarding the relative effective-ness of first and second generation antipsychotics forschizophrenia is predominantly based on short-term stud-ies and does not adequately address long-term effective-ness and cost issues. The studies of second generationantipsychotics to date, which have for the most part beensponsored by pharmaceutical companies and designed toachieve regulatory approval based on evidence of efficacyand safety, typically have lasted 4 to 12 weeks, haveinvolved initially hospitalized patients with no medical orpsychiatric comorbidities, and have permitted few con-comitant medications. The main outcome measures ofthese studies have mainly been the core psychopathologyof schizophrenia and well-known side effects (e.g.,

Send reprint requests to Dr. T. S. Stroup, CB# 7160, 10626Neurosciences Hospital, University of North Carolina at Chapel Hill,Chapel Hill, NC 27599-7160; e-mail: [email protected].

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Schizophrenia Bulletin, Vol. 29, No. 1, 2003 T.S. Stroup et al.

extrapyramidal side effects [EPS]) that are particularlyproblematic for some of the first generation drugs. Thesestudies have neither definitively demonstrated the "realworld" effects of the newer atypical antipsychotics in thebroad patient populations that receive them nor adequatelyexamined the broad range of side effects that may occur.The limited types of assessment measures used and shortstudy durations have not provided adequate informationabout treatment for this highly variable and chronic condi-tion. Moreover, the patient samples involved in these stud-ies and the conditions imposed by the restrictions of theprotocols limit the generalizability of the results. Addi-tional information is needed to inform clinicians about theappropriate role of atypicals. Because atypical antipsy-chotic medications represent a major budget item forhealth benefit plans, including State Medicaid agencies,objective information about their cost-effectiveness isdirely needed by policy makers.

Consequently, as part of its public mental health caretreatment initiative, the National Institute of Mental Health(NIMH) established a request for proposal (RFP) for aresearch program to evaluate the comparative effective-ness of antipsychotic drugs in disorders for which thisclass of drugs is indicated (RFP 99-DS-0001) (seeLebowitz et al., this issue). The RFP issued by the NIMHspecified that the protocol should focus on atypicalantipsychotic drugs and should follow a public healthmodel. In particular, the RFP specified that the trial shoulddo the following: focus on effectiveness and broader mea-sures of outcome rather than efficacy alone; examine cost-effectiveness and the impact of external factors on treat-ment delivery, adherence, and outcomes; enhancegeneralizability by being as inclusive as possible, withoutexclusions for comorbid psychiatric disorder, drug abuse,or medical illness; place a premium on demographic andgeographic diversity; use multiple types of treatment set-tings that generally represent the systems of care in whichpatients with schizophrenia are treated; and generateresults that inform community clinical practice. In addi-tion, the RFP called for the program to develop a networkof sites and investigators able to respond to future needsfor effectiveness research, to serve as a base for ancillaryclinical investigations, and to include a mechanism foradding new antipsychotic medications in the future. TheClinical Antipsychotic Trials of Intervention Effectiveness(CATTE) program was funded through a contract awardedto the University of North Carolina (UNC).

This article describes the development of the studydesigned to assess the effectiveness of antipsychotic drugsfor persons with chronic schizophrenia. (The article bySchneider et al. in this issue describes the development ofthe study designed to assess the effectiveness of antipsy-chotic drugs for persons with Alzheimer's disease with

agitation and psychosis.) Soon after the contract periodbegan in October 1999, the original group of investigatorsat UNC, Duke, and Yale expanded the Protocol Develop-ment Committee by including other schizophreniaresearchers who were not part of the original team. Thetrial designs submitted in the contract application processwere a starting point for the protocol development process.An initial day-long meeting of the committee took place inChapel Hill, NC (November 1999), with subsequentweekly meetings held by teleconference. In this way, theprotocol was developed by the CATTE team of investiga-tors through an iterative, systematic process. Additionalinput was sought from various "stakeholder" groups,including consumer representatives, mental health careadministrators, and policy makers.

In January 2000, a draft study design was presented toconsumer representatives at an NIMH-convened workshopentitled Clinical Trials Recruitment: What Motivates Peo-ple to Participate? Feedback from this meeting led to sub-stantial protocol modifications. In March 2000, a reviseddraft protocol was submitted to the NIMH for review byits Scientific Advisory Committee for the CATDE program.This committee made additional recommendations thatwere incorporated into the final protocol.

Rationale for Trial DesignThe CAllfc schizophrenia trial addresses the aims of theCATTE RFP. It seeks to fill some of the existing gaps intranslating efficacy to effectiveness. To do this, the studyhas adapted many of the characteristics of "pragmatic"randomized controlled trials (RCTs). Pragmatic RCTs aimto answer "real-life" questions of practical significance toclinicians and patients in real-world clinical settings(Hotopf et al. 1999). Such settings have varied levels ofancillary services and serve patients with comorbid psy-chiatric illnesses, general medical problems, and substanceuse disorders. Medication adherence is not ensured, as isthe case in routine practice. However, such pragmaticstudies randomize interventions and endeavor to ensurethat treatments and the assessment of outcomes areblinded where possible.

The primary aim of the CATIE schizophrenia trial isto determine the comparative effectiveness of a representa-tive conventional antipsychotic and the different atypicalantipsychotic medications for a representative sample ofpatients seeking treatment for chronic schizophrenia asmeasured by all-cause treatment discontinuation rates andassociated measures of effectiveness and safety. Potentialcauses for discontinuation include a clinical determinationof inadequate therapeutic effect (efficacy failure) or unac-ceptable side effects (tolerability failure), patient inabilityor refusal to take the assigned antipsychotic (adherence/

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The NIMH-CATIE Project Schizophrenia Bulletin, Vol. 29, No. 1, 2003

compliance), and administrative reasons (e.g., subjectmoves out of the study area). Further, if differential dis-continuation rates occur among the medications, the studyis designed to identify key causes for discontinuation.

In the protocol development process, study designdecisions were made by the Schizophrenia ProtocolDevelopment Committee with input from various "stake-holder" groups. Some of the key design decisions and theirrationales are reviewed below.

Patient Sample. To make the results of the trial general-izable and representative of the broad group of chronicschizophrenia patients, there are few exclusion criteria.Patients with medical or psychiatric comorbidities andthose who require concomitant other medications areincluded in the trial.

The patients who enroll in this study have chronic orrecurrent schizophrenia. First episode patients and whollytreatment-refractory patients are excluded. First episodepatients are excluded because of their high rates of responseto antipsychotic medications at relatively low doses. Treat-ment-refractory patients are excluded because their severeillness may preclude detection of differential effectivenessthat would be apparent in treatment-responsive patients.

A wide spectrum of patients with schizophrenia enrollin the study, ranging from partially remitted outpatients toexacerbated inpatients. Partially remitted patients, whohave received benefit from antipsychotic medication butwho remain symptomatic (because of lack of efficacy orinability to tolerate an efficacious dose) or who suffer sig-nificant side effects, commonly consider a change in med-ications. Patients whose condition is exacerbated alsocommonly need a change in medication. Patients who areseemingly doing well on their current medication but whowish to consider a change for reasons of greater improve-ment or better tolerability also enroll.

Inclusion of Conventional Antipsychotic Medications.This study offers an important opportunity to determinewhether atypicals are indeed superior to conventionalantipsychotic drugs. Perphenazine was selected as theconventional medication because it is a midpotency med-ication with only a moderate incidence of EPS (relative tohigh-potency medications and other midpotency medica-tions) and sedation (relative to low-potency medications).We considered the appropriateness of assigning patientsentering the study on atypical medications to a conven-tional antipsychotic. Because our aim of determining therelative real-world effectiveness of conventional and atyp-ical antipsychotic medications is critical to clinicians andpolicy makers, we determined that only tardive dyskinesia(TD) is a contraindication for this treatment decision.Therefore, patients with TD are excluded from the arm of

the study that allows random assignment to a conventionalantipsychotic. In phase 1, patients with TD enter phase1A, which includes randomization to only oral olanza-pine, quetiapine, risperidone, or ziprasidone.

Long-acting intramuscular forms of conventionalmedications were carefully considered for inclusion in thisstudy. A depot comparison gained strong support becauseof its clinical relevance for persons with a history of med-ication nonadherence or substance abuse, or with an unsta-ble living situation. Ultimately, however, the followingfactors led to the decision not to include a depot compari-son group in phase 1:

• The expectation that a depot form of an atypicalmedication would soon be marketed, limiting thefuture significance of our findings

• The difficulty of blinding injections and possiblebias against the unblinded (or blinded) treatments

• The problem of testing a treatment indicated forpatients with a history of medication nonadher-ence in a study that requires all patients to agreeto take medications

• The expected difficulty of enrolling participantsin a depot study with a conventional medication

Ultimately, we concluded that a comparison of oral todepot medications would not be a primary goal of thisstudy and that the effectiveness of depot medicationsshould be examined in a study primarily focused on thatquestion.

Double-Blinded Treatment Conditions in Phases 1 and2. The treatments in phases 1 and 2 are blinded (exceptfor clozapine) to enable rigorous comparisons of treat-ment effectiveness between drugs. The rationale for blind-ing is sufficiently compelling despite the complications itintroduces to the study's practical implementation and itsecological validity. Because the oral medications used inphases 1 and 2 have been marketed for several years, clin-icians and patients have preconceived notions about theefficacy and side effect profiles of the medications.Therefore, oral medications are blinded and physicians,raters, and patients do not know which medication hasbeen assigned to an individual. This is intended todecrease bias in ratings and biased decisions about treat-ment failure. Clozapine is open label because of the logis-tical complexities that bunding it would involve given theneed for blood sampling for hematologic monitoring.

Patient and Clinician Involvement in Decision Making.In response to feedback from consumer and advocacygroups to an earlier version of this protocol at the NTMH-convened workshop mentioned above, it was decided toinclude participant input when determining possible treat-

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ment options. Consumer advocates suggested that thisfeature would make the study more appealing to con-sumers and their family members and thus would improveenrollment and retention rates. When participants enterphase 2, they choose between two studies, one that com-pares clozapine to the other atypical medications not pre-viously taken in the CATIE study, and another that com-pares ziprasidone to the other atypical medications notpreviously taken. In addition, subjects and their cliniciansmake a shared decision about an appropriate open-labeltreatment in phase 3. When a participant enters phase 3,partial information about phase 1 and phase 2 treatmentassignments is given to the study clinicians and patientsso that an informed treatment decision can be made basedon previous experience in the study. The names of thephase 1 and phase 2 drugs are provided alphabeticallyrather than chronologically in order to help preserve theblind.

Augmentation With a Second Antipsychotk Medication.Simultaneous treatment with two antipsychotics is avail-able in phase 3 as a result of feedback that the ProtocolDevelopment Committee received from numerous stake-holders, including several mental health care administra-tors and policy makers, who reported that combiningantipsychotic drugs is a common treatment strategy whenresponse to a single antipsychotic is suboptimal. We willobtain descriptive information about this treatment strat-egy because dual antipsychotic treatment is included as anoption in phase 3. The results may help decide whether toinclude a two-antipsychotic arm in future CATTE trials.

Primary Outcome Variable. Time to all-cause treatmentfailure, marked by its discontinuation, was selected as theprimary outcome variable. Although symptoms, sideeffects, functioning, costs, and so on are important out-comes, we chose treatment discontinuation as the primaryoutcome because it is a distinct measure that reflects bothefficacy and side effects. All-cause treatment discontinua-tion is a clinically meaningful outcome that reflects theinput of both the patient and the clinician. In the course ofa patient's treatment, the need to change medicationsreflects the possibility that the treatment was not suffi-ciently effective or tolerable, or the belief that anothertreatment would be superior.

Guidelines ensure that physician-initiated treatmentchanges are made for only logical and justifiable reasons,so that each treatment to which patients are assigned isgiven every chance to be effective before a switch is made.Guidelines also are provided to help ensure that cliniciansand patients attempt to optimize dosing and use adjunctivemedications before determining that the drug is not usefulor tolerable. The goal is for patients to be withdrawn from

a study medication only when guideline-recommendedtreatment options have been exhausted and clear clinicaldeterioration persists, or for administrative reasons.Although participant retention is important, the safety andwell-being of individual patients are the primary consider-ations in all clinical decision making.

Inclusion of Newly Approved Antipsychotics. Becauseof our desire that the CATEE trials be maximally informa-tive regarding current clinical practice, we made contin-gency plans to include, if possible, new antipsychoticdrugs that gained U.S. Food and Drug Administration(FDA) approval during the study's enrollment period. InFebruary 2001, ziprasidone was approved by the FDA andwas then added to phases 1, 2, and 3 of the study. InNovember 2002 aripiprazole was approved by the FDAand was then added only to phase 3 as an open-label treat-ment. Thus we expect information from randomized,blinded portions of the trial about ziprasidone, but willobtain only open-label, descriptive data about aripipra-zole.

Methods

Specific Aims and Hypotheses. The specific aims of theschizophrenia trial are as follows:

• To determine the long-term effectiveness and tol-erability of the newer atypical antipsychotics, rel-ative to perphenazine. We hypothesize that treat-ment with the newer atypical antipsychotics isassociated with greater long-term effectivenessand tolerability than treatment with per-phenazine.

• To determine the comparative long-term effec-tiveness and tolerability of the newer atypicalantipsychotics in adults with schizophrenia. Wehypothesize that the newer atypical antipsy-chotics are similarly effective in treating psy-chopathology but have different side-effect liabil-ities.

• To determine, among patients who fail treatmentwith an initially assigned newer atypical antipsy-chotic, the long-term effectiveness and tolerabil-ity of the newer atypical antipsychotics, relativeto clozapine. Patients with inadequate resolutionof psychopathology, or marked sensitivity toEPS, are recommended to enter this phase 2 trial.We hypothesize that treatment widi clozapine isassociated with greater long-term effectivenessand tolerability than treatment with a newer atyp-ical drug other than the one the patient initiallyreceived.

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• To determine, among patients who fail treatmentwith an initially assigned newer antipsychotic,the long-term effectiveness and tolerability of thenewer atypical antipsychotics, relative to ziprasi-done. Patients with weight gain, hyperglycemia,or hyperlipidemia are recommended to enter thisphase 2 trial. We hypothesize that treatment withziprasidone is associated with greater long-termeffectiveness and tolerability than treatment witha newer atypical drug other than the one thepatient initially received.

Study Design. The CATTE schizophrenia trial is a multi-phase RCT of antipsychotic medications involving up to1,500 persons with schizophrenia followed for 18 months.Figure 1 contains a schematic diagram of the trial design.Participants are broadly representative of persons with thechronic and recurrent forms of schizophrenia. Patients areto be followed for at least 18 months. The study includesthree treatment phases and a naturalistic followup phase.Persons who do well on an assigned treatment remain onthat treatment for the duration of the 18-month treatmentperiod. If an assigned treatment is deemed a failure, thepatient moves to the next phase of the study to receive anew treatment. All study medications are double-blinded

in treatment phases 1 and 2 except for clozapine, which isdispensed open label because of the clinical requirementto monitor maintenance of adequate white blood cellcounts.

Outcome measures for the trial extend beyond effi-cacy and safety to capture more details about participants'quality of life, cognitive capacity, and use of general, men-tal health, substance abuse, and rehabilitative services. Therepresentativeness of the subjects is ensured by recruitinginto the trial a broad range of "real-world" patients,including those with comorbid conditions (e.g., substanceuse disorders, medical problems) that would exclude themfrom most clinical trials. The study is being conducted atsites that represent a broad array of clinical settings (e.g.,State mental health, academic, Department of VeteransAffairs, health maintenance organization, managed care)in order to generate representative, generalizable, andpractically relevant study findings.

In phase 1 of the trial, patients are randomly assignedto double-blinded treatment with oral perphenazine,oianzapine, quetiapine, risperidone, or ziprasidone.Patients with TD bypass phase 1 (and the risk of assign-ment to perphenazine) and are assigned to treatment withoral oianzapine, quetiapine, risperidone, or ziprasidone(phase 1A).

Figure 1. Schizophrenia trial design. Responders stay on assigned medication for duration of 18-month treatment period. Phase 1A = Participants with tardive dyskinesia are not randomized to per-phenazine; phase IB = Participants who fail to respond to perphenazine are randomized to an atypical(oianzapine, quetiapine, or risperidone) before they are eligible for phase 2; R = randomized.

1,500participants

withschizophrenia

Phase;!

Double-blind, randomtreatment assignment

OLANZAPINE

QUETIAPINE

RISPERIDONE

ZIPRASIDONE

PERPHENAZINE

Phase 2 Phase 3

Participants who discontinuephase 1 choose either the

clozapine or the ziprasidonerandomization pathways

CLOZAPINE(op«n label)

OLANZAPINE,QUETIAPINE, orRISPERIDONE

ZIPRASIDONE

OLANZAPINE,QUETIAPINE, orRISPERIDONE

No one assigned to samedrug as in Phase 1

Participants who discontinuephase 2 choose one of the

following open-label treatments

•ARIP1PRAZOLE•CLOZAPINE

•FLUPHENAZINEDECANOATE

•OLANZAPINE

•PERPHENAZINE

•QUETIAPINE

•RISPERIDONE

•ZIPRASIDONE

•Two of the aboveantipsychotics

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Participants who discontinue treatment with the con-ventional antipsychotic (oral perphenazine) in phase 1 arerandomly assigned to double-blinded treatment witholanzapine, quetiapine, or risperidone (phase IB).

In phase 2, participants who discontinue their assignedtreatment with an atypical antipsychotic in phase 1,1A, or IBare recommended to one of two treatment assignment path-ways based on their reason for discontinuation, as follows:

• The first pathway in phase 2 offers a 50:50 random-ization to ziprasidone versus one of the other atypi-cal antipsychotics (olanzapine, quetiapine, or risperi-done) not previously received by the patient in thisstudy. Patients who discontinued their previous treat-ment with an atypical antipsychotic because of intol-erance to the previous regimen (e.g., weight gain) areexpected to preferentially enter this study.

• The second pathway in phase 2 offers a 50:50 ran-domization to clozapine versus an atypical antipsy-chotic (olanzapine, quetiapine, or risperidone) notpreviously received by the patient in this study.Patients who discontinued their previous treatmentwith an atypical antipsychotic because of inadequateefficacy are expected to preferentially enter thisstudy.

Phase 3 is for persons who discontinue the treatmentassigned in phase 2. Research and clinical staff examine rea-sons for failure of the treatments assigned in phases 1 and 2.Based on this review, study treatment guidelines are reviewedand the research participant is followed in phase 3 on anopen-label treatment chosen collaboratively by the clinicianand patient.

The followup phase is for persons who are no longer will-ing to continue taking study medication or who have discontin-ued their phase 3 medication before 18 months from the timeof initial randomization has elapsed. Followup phase partici-pants are not provided with study medication but are followednaturalistically on their treatment of choice. Fbllowup visits tocollect basic outcome data are scheduled quarterly through 18months from the time of a participant's initial randomization.

Subjects. A sample of 1,500 men and women, 18 to 65years of age, who currently meet or have met in the pastDSM—IV diagnostic criteria for schizophrenia, based uponthe Structured Clinical Interview for DSM-IV (SCID;First et al. 1994), review of their clinical records, andinput from available informants, are enrolled. Inclusionand exclusion criteria are listed in tables 1 and 2.

TreatmentsPharmacological treatments.Dosing of study medications. Standard study capsules

contain olanzapine 7.5 mg, quetiapine 200 mg, risperi-

done 1.5 mg, ziprasidone 40 mg, or perphenazine 8 mg(table 3). Clinicians can prescribe one to four capsulesdaily, based on individual patients' therapeutic responseand side-effect burden.

Once and twice daily medication schedules.Quetiapine and ziprasidone require twice daily (BED) dos-ing, whereas perphenazine, olanzapine, and risperidonecan be taken once daily (QD). Because it would deviatefrom clinical practice patterns to insist on BID dosing inall cases, we sought to minimize the number of patientswho are required to take their medication BID, and stillmaintain blinding to the extent possible. Throughout thestudy, half of the patients randomized to perphenazine,olanzapine, and risperidone are assigned to BID dosing,and half are assigned to QD dosing. All quetiapine andziprasidone patients receive BID dosing unless they aredetermined to need only one capsule per day.

Because quetiapine has a relatively slow recom-mended initial titration schedule, patients assigned to aBID dosing schedule begin their treatment using an initialdose strength and follow the titration schedule described intable 4. After the initial titration period using a starter packof capsules, the total BID dose of all blinded study med-ications is identical to the QD dosing schedule. It isexpected that there will be roughly equal efficacy andsafety responses for the QD and BID dosing of these med-ications.

Dosing for open-label medications. As noted in table5, the recommended dose range for open-label clozapinein phases 2 and 3 is 200 to 600 mg daily. The recom-mended dose range for fluphenazine decanoate injectionsavailable in phase 3 is 12.5 to 50 mg intramuscularly (IM)every 2 weeks for most patients. The recommended doserange for aripiprazole in phase 3 is 10 to 30 mg daily.

Transition to study medications. Because this studyaddresses long-term effectiveness and tolerability, notacute treatment efficacy, efforts are made to facilitate thetransition of patients onto their study medications and pre-vent their destabilization by this process. For patients whoare already taking an antipsychotic medication prior to anyphase, tapering the previous medication over 2 weeks isrecommended, but cross-titration is permitted for up to 28days. Clinicians have substantial leeway in implementingthese transitions according to clinical judgment.

Summary of pharmacological treatments. The meth-ods allow double-blind comparisons among the neweratypical antipsychotics, and between the newer atypicalantipsychotics and perphenazine. The blinding proceduresallow dosing across commonly prescribed dose ranges ofthe study drugs (olanzapine 7.5-30 mg daily, quetiapine200-800 mg daily, risperidone 1.5-6 mg daily, ziprasidone40-160 mg daily, and perphenazine 8-32 mg daily) withequivalent numbers of capsules, that is, one to four daily.

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Table 1. Inclusion criteria

1. Patients must be 18-65 years of age.

2. Patients must currently meet or have met in the past the DSM-1Vcriteria for schizophrenia.

3. Patients entering the study must, according to their own judgment in consultation with their physician, have a conditionappropriate for treatment with an oral medication.

4. Patients must demonstrate adequate decisional capacity to make a choice about participating in this research study andmust provide informed consent to participate.

Table 2. Exclusion criteria

1. Patients with a DSM-tVdiagnosis of schizoaffective disorder, mental retardation, pervasive developmental disorder,delirium, dementia, amnesia, or other cognitive disorders are excluded.

2. Patients with well-documented, drug-related, serious adverse reactions to even one of the proposed treatment armsare excluded.

3. Patients in their first episode of schizophrenia are excluded. Patients will be considered to be in their first episode ifthey first began antipsychotJc drug treatment for psychosis within the previous 12 months and have had psychoticsymptoms for less than 3 years.

4. Patients with well-documented histories of failure to respond to even one of the proposed treatment arms areexcluded. A treatment failure has occurred If the patient continued to demonstrate severe psychopathology in spite offully adhering to treatment at an adequate dose of the medication for an appropriate length of time. Specific dose andduration criteria are as follows:

• Olanzapine at dosages £ 30 mg/day for 6 consecutive weeks• Quetiapine at dosages £ 800 mg/day for 6 consecutive weeks• Perphenazine at dosages £ 32 mg/day for 6 consecutive weeks• Risperidone at dosages £ 6 mg/day for 6 consecutive weeks• Ziprasidone at dosages £ 160 mg/day for 6 consecutive weeks

5. Patients currently, or in the past, treated with clozapine for treatment resistance are excluded. Patients who have takenclozapine for reasons other than treatment resistance may be eligible.

6. Patients who are currently stabilized on haloperidol decanoate or fluphenazine decanoate and who require long-actinginjectable medication to maintain treatment adherence are excluded.

7. Women who are pregnant or breastfeeding are excluded. Women of childbearing potential must agree to use appropri-ate contraception in order to enroll in this study.

8. Patients with tardive dyskinesia are excluded from assignment to conventional antipsychotic treatment arms.

9. Patients with a contraindication to any of the drugs to which they might be assigned are excluded.

10. Patients with a medical condition that is serious and acutely unstable are excluded.

11. Patients with the following cardiac conditions are excluded:

• Recent myocardial infarction (<6 months)• QTc prolongation (screening electrocardiogram with QTc > 450 msec for men, QTc > 470 msec for women)• History of congenital QTc prolongation• Sustained cardiac arrhythmia or history of sustained cardiac arrhythmia• Uncompensated congestive heart failure• Complete left bundle branch block• First-degree heart block with PR interval £ 0.22 seconds

12. Patients on concurrent treatment with dofetilide, sotalol, quinidine, other Class la and III antiarrhythmics, mesoridazlne,thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatjfloxacin, moxifloxacin, halofantrine, mefloquine,pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, or tacrolimus are excluded.

13. Patients who have taken any investigational drug within 30 days of the baseline visit are excluded.

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Table 3. Standard study dosing

Blinded medications Dose per standard study capsule Dose range

OlanzapinePerphenazineQuetiapineRisperidoneZiprasidone

7.5 mg8mg

200 mg1.5 mg40 mg

7.5-30 mg/day8-32 mg/day

200-800 mg/day1.5-6 mg/day

40-160 mg/day

Table 4. Initial

Blindedmedications

twlce-a-day dosing

Initial dosagecapsules

schedule

Day1

Dally

Day 2

Dose (mg) During

Day 3

BIDTttratlon

Day 4 a.m. Day 4 p.m.

Olanzapine 7.5 mgPerphenazine 8 mgQuetiapine 100 mgRisperidone 1.5 mgZiprasidone 40 mg

Note.—BID = twice a day; QD = once a day.

Table 5. Recommended dosing for open-labelstudy medications

Open-label medications Dose range

7.5 QD8QD

100 QD1.5 QD40 QD

7.5 QD8QD

100 QD1.5 QD40 QD

7.5 BID8 BID

100 BID1.5 BID40 BID

7.58

1001.540

7.58

2001.540

Fluphenazine decanoateClozapineAripiprazole

12.5-50 mg every 2 weeks200-600 mg/day10-30 mg/day

This design also allows comparison of QD versus BIDdosing strategies.

Clinicians can adjust the dose of the assigned antipsy-chotic as clinically indicated within the range of one to fourstandard study capsules. Clinicians can prescribe adjunctiveand concomitant medications whenever they believe theseare indicated, but they must record the indications for theiruse. Antipsychotics other than the assigned study medicinesare not allowed. The antipsychotic cannot be discontinued orchanged without considering the treatment a failure. Addi-tional antipsychotics may not be prescribed after cross-titra-tion is complete except in emergencies or in phase 3 ifpatients elect the dual antipsychotic treatment option. Theongoing need for an additional antipsychotic is a criterion fortreatment failure.

Psychosocial Interventions. Meta-analytic reviews (e.g.,Mojtabai et al. 1998) support the additive effectiveness ofpsychosocial treatments delivered in combination withpharmacological treatment. Adding a psychosocial treat-ment produces greater improvement on measures of out-come than pharmacological treatment alone. The additionof a psychosocial treatment decreases relapse rates by 20percent, on average, relative to medication treatmentalone.

Research participants are offered psychosocial inter-ventions directed at improving patient and family under-standing of the illness, decreasing the burden of illness onthe family, maximizing treatment adherence, minimizingrelapse, enhancing access to a range of community-basedrehabilitative services, and improving study retention.Interventions include the following:

• Patient and family education• Opportunities for family support• Adherence enhancement• Broker/Unking style case management or liaison

with existing case management services

Patient and family education. All participants areoffered an individually tailored educational plan adaptedfrom the successfully implemented Texas MedicationAlgorithm Project (TMAP). The TMAP education plan isconducted in several phases and invites family participa-tion if desired by the patient. Each phase involves one ormore individual sessions, with patients moving to the nextphase as appropriate. All sessions are presented orally,with supplementary print materials offered. Videotapeeducational presentations are also made available. Toassess the intensity of educational efforts, research stafflog the educational sessions provided to each subject.

The phases of the educational plan include the follow-ing:

• Individual introductory education. Contentincludes diagnosis, medications, and symptomself-monitoring.

• Individual followup. Content includes self-assessment of symptoms and side effects, assess-ing changes in symptoms, and so forth.

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• Ongoing education. Content includes more exten-sive information about the illness, and treatmentand reinforcement of earlier content.

• Group education/support. This phase offersopportunities for patients to discuss the illnesswith each other and provides referrals to othersupport groups.

Family support. Study sites are encouraged to workwith the National Alliance for the Mentally 111 (NAMI) tofacilitate offerings of family support groups at study sitesor in the local community. Where feasible, structured fam-ily education programs (Journey or Hope/Family-to-Family program) are also offered.

Adherence enhancement Kemp et al.'s (1996) com-pliance therapy intervention was adapted for CATTE toguide and enhance patient and family education on med-ication adherence. This cognitive behaviorally orientedapproach equips therapists to address common problemswith denial of illness and resistance to treatment. In theinitial phase, the patient's stance toward treatment iselicited. In the second phase, ambivalence to treatment isexplored, common misgivings are addressed, misconcep-tions are corrected, and indirect benefits of medicationsare emphasized. The third phase of compliance therapyfocuses on treatment maintenance. Research associatesand study clinicians have access to adherence enhance-ment materials on the CATTE Web site.

Case management. Sites vary in case managementavailability. Nonetheless, all participants have access tolocally available community-based treatment and rehabili-tative services so as to maximize potential rehabilitationand functioning. For subjects with active case manage-ment, study sites do not duplicate these services but serveas a liaison to ongoing case management services. Wheresubjects do not have case management provided, site per-sonnel serve as broker/linking style case managers,attempting to gain entry for subjects to community ser-vices.

Measures and Assessment of Outcomes. Subjects attendmonthly study visits for clinical examinations and to par-ticipate in assessments following the study's Schedule ofEvents (table 6). Outcome measures are obtained from avariety of sources, including patient self-report, clinicianratings, and ratings by trained study personnel.

Clinical and functional assessments.Primary outcome. Time to all-cause pharmacological

treatment failure, reflected by a decision to discontinueand change medications, is the primary outcome in thestudy. For time to withdrawal to serve as a meaningfulvariable, treatment retention must be maximized. There-fore, except under unusual circumstances, patients are

withdrawn from the study only when treatment optionshave been exhausted and clear clinical deterioration per-sists. Nonadherence, exacerbation of psychopathology, orhospitalization do not necessarily require diat a patient bewithdrawn from the treatment that he or she is receiving inthe study (e.g., if a patient experiences a recurrence ofsymptoms because he or she went away on a trip for 1week and forgot to bring the medication and therefore didnot take it). Similarly, only a side effect that produces sig-nificant subjective distress or objective dysfunction thatcannot be resolved by dose adjustment or adjunctive med-ications should lead to treatment discontinuation. How-ever, this focus on patient retention is balanced by the factthat the safety and well-being of patients are the primaryconsiderations in all clinical decision making. Under nocircumstances are patients maintained on their currentstudy medications if there is a clear clinical reason tochange or they prefer to move on to the next phase of thestudy or discontinue study medication or participationaltogether.

In addition to this primary outcome measure, the clin-ical and functional outcome measures listed in table 7 areused to assess psychopathology, recovery, relapse, andseverity of illness over the course of the study. Descrip-tions of these measures and the rationales for their selec-tion appear in the article by Swartz et al. in this issue.

Side effects and adverse events measures. In addi-tion to the measures listed in table 7, metabolic effects ofthe drugs are monitored regularly. Each participant'spulse, blood pressure, and weight are assessed regularly.To evaluate the effect of antipsychotic treatments onweight gain, glucose and lipid metabolism, waist-hip ratio(WHR), and body-mass index (BMT) are recorded regu-larly. In addition, fasting blood glucose level, hemoglobinA1C, lipid profile (total cholesterol, high-density lipopro-tein [HDL] cholesterol, triglycerides), complete bloodcount, and serum prolactin level are collected according tothe Schedule of Events (table 6).

Adverse events and side effects. Given the substantialclinical experience already available with these drugs, weelected to focus our monitoring on 18 well-known adverseevents and side effects (AE/SE) that have been commonlyreported with one or more of the study antipsychotics. Byasking systematically about these 18 AE/SE, we willdetermine the relative frequencies and severities of thesecommon and important AE/SE across the study antipsy-chotics. However, we also included a general inquiry sec-tion to record responses to questions about general physi-cal health.

Family/caregiver experiences. Family burden ismeasured to assess the impact of schizophrenia on theobjective and subjective burden on the family using arevised version of the Family Experiences Interview

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Schedule (Tessler and Gamache 1995). Families andcaregivers are asked about instrumental support pro-vided, limit setting provided for disturbing behavior,time spent directly related to care for the patient, lostproductivity, and financial contributions to the patient'scare.

Medication adherence. Medication adherence isconceptualized as an intermediate outcome variable in thisstudy. However, because adherence with treatment is aprerequisite for determining the effectiveness of the studymedications as indicated by all other outcome measures,efforts are made to maximize participant adherence tomedication regimens. Although these efforts to enhanceadherence may confound the assessment of adherence asan outcome measure, relative to usual care, they do soequally across all treatment groups.

To enhance understanding of the relationship betweenpatient attitudes toward medications, insight into illness,and medication adherence, we administer the Drug Atti-tude Inventory (Awad 1993) and the Insight Into Treat-ment Attitude Questionnaire (McEvoy et al. 1989) at inter-vals specified in the Schedule of Events (table 6).

A pill count is conducted monthly. The patient isasked a standard set of questions about medication adher-ence at each appointment. Study personnel synthesize thepatient report, pill count, and any other available informa-tion into a global judgment of medication adherence.

Substance use. Substance use is examined in multi-ple ways. Subjects are asked quarterly about drug andalcohol use. Urine drug screens are performed quarterly.In addition, hair samples for radioimmunoassay to detectsubstances of abuse are collected during patient visits andshipped to a central laboratory for assessment

Neurocognitive assessments. Because the choice oftests for a neurocognitive battery is often controversial,the tests were chosen with consensus approval from theleaders in schizophrenia and dementia research. ANeurocognitive Advisory Group was selected in concertwith the NIMH project officer and the External ScientificAdvisory Board. Selection of members was designed toensure maximum consensus and integration of personnelacross committees.

The neurocognitive battery is completed according tothe Schedule of Events in table 6. The tests are listedbelow.

• WRAT-m Reading Test (Wilkinson 1993)• Controlled Oral Word Association Test (Benton

and Hamscher 1978)• Category Instances (Category Fluency) (Benton

and Hamscher 1978)• Wechsler Intelligence Scale for Children-

Revised, Mazes (Wechsler 1991)Hopkins Verbal Learning Test (Brandt 1991)

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Table 7. Clinical and functional outcome measures

Psychopathology

Adverse events/side effects

Psychosocial

Family experiences

Clinical Global Impressions Scale—Severity and self-report versions

Positive and Negative Syndrome ScaleCalgary Depression Rating Scale1

Barnes Akathisia Scale2

Simpson-Angus Extrapyramidal Side Effect Scale3

Abnormal Involuntary Movement Rating Scale

Adverse events/side effects form

Heinrichs-Carpenter Quality of Life Scale4

Lehman Quality of Life Interview—selected items5

MacArthur Community Violence Instrument6

Medical Outcomes Study Short Form-12Insight Into Treatment Attitude Questionnaire

Drug Attitude Inventory

Family Experiences Interview Schedule (adapted)

1Addlngton et al. 1990.2Barnes 1989; Carpenter et al. 2000.Simpson and Angus 1970.4Heinrichs et al. 1984.6Lehman1988.6Steadman et al. 1998.

• Face Emotion Discrimination Task (Kerr andNeale 1993)

• Wechsler Adult Intelligence Scale-Digit SymbolTest (Wechsler 1974)

• Letter-Number Span (Gold et al. 1997)• Grooved Pegboard (Lafayette Instrument Com-

pany 1989)• Computerized Continuous Performance Test

(Cornblatt et al. 1988)• Computerized Test of Visuospatial Working

Memory (Hershey et al. 1999)• Computerized Wisconsin Card Sorting Test

(Heaton et al. 1993)

These tests and the neurocognitive functions measuredby them are described by Keefe et al. elsewhere in this issue.

Health services and cost-effectiveness assessments.External factors such as the contacts between the patientand his or her health care setting and psychosocial supportsystem (including family interactions, living situation,environmental safety, and financial resources) may affectoutcomes and also reflect the effectiveness of treatments.The methods used to examine the organizational contextof care, the subject service utilization, and the basis forthe study's cost-effectiveness and cost-benefit analyses inCATIE are outlined by Schneider et al. (2001) in an arti-cle describing the Alzheimer's disease trial and used byRosenheck and colleagues elsewhere (Rosenheck et al.1997, 1999). These methods are summarized here.

The high cost of atypical antipsychotic medicationscan be justified if their use leads to savings in other healthcare or non-health care costs or if they yield improve-ments in the well-being of patients, their families, or thecommunities in which they live. Cost analyses will be con-ducted from the perspective of society and will include thecost of medications and all other health care costs.

Costs will be measured as the product of the units ofservice X the cost per unit, and will be assessed throughthe Service Use and Resources Form (SURF; Rosenhecket al. 1998). The SURF comprehensively documents useof health services and non-health resource consumptionsuch as involvement with the criminal justice system andpublic support payments. We will conduct a series of sen-sitivity analyses using different unit-cost estimates. Med-ication costs will be based on the specific dosing of allagents to each patient.

Effectiveness will be evaluated in two ways. First, wewill use the utilities generated by the Health Utilities Index(HUI; Feeny et al. 1996), a health-related quality-of-lifeindex that measures preference-based utilities and healthstates in quality-adjusted life years (QALYs). Second, wewill combine other quality-of-life and symptom measuresand scale them to generate disease-specific QALYs, usingmethods developed elsewhere (Rosenheck et al. 1998).Sensitivity analysis will be conducted using both measuresof effectiveness.

Initially, costs and effectiveness measures will beexamined separately. If the increased medication costs of

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atypical antipsychotics are offset by reduced servicescosts, and outcomes are superior, then the atypical antipsy-chotics will emerge as dominant choices and further analy-sis will not be necessary. If both costs and benefitsincrease with atypical antipsychotics, further analysis willbe undertaken using cost-effectiveness acceptabilitycurves (Van Hout et al. 1994). These analyses take intoconsideration various estimates of the monetary value of aQALY and estimate the probability of achieving variouscost-effectiveness ratios.

Safety

Serious adverse events, as defined by the FDA, areassessed according to FDA guidelines. Treatment-emer-gent adverse effects are monitored using the AE/SE mea-sure described above.

Clinical Monitoring and Laboratory Tests. The sched-ule for clinical monitoring and laboratory testing appearsin the Schedule of Events (table 6). Screening evaluationsare intended to identify medical abnormalities and toestablish baseline levels. Parameters to be monitoredinclude clinical chemistry and electrolytes (sodium, potas-sium, bicarbonate, chloride, blood urea nitrogen, creati-nine, phosphorus, uric acid, calcium, total protein, albu-min, creatine kinase, alkaline phosphatase), liver functiontests, thyroid-stimulating hormone, complete blood count,urinalysis, fasting blood glucose, lipids (total cholesterol,HDL cholesterol, and triglycerides), urine pregnancy test(for all women), prolactin, and an electrocardiogram(ECG). Laboratory assessments are collected andprocessed via a central laboratory, while ECGs areprocessed through a central ECG laboratory.

Each patient's pulse, blood pressure, and weight arerecorded at screening, month 1, and month 3, and quar-terly thereafter. Height is recorded at screening. To evalu-ate the effect of antipsychotic treatments on weight gain,we calculate the WHR and the BMI on this same schedule.In addition to the screening ECG, an ECG is conducted atthe month 18 visit, at each end-of-phase visit, and 1 monthafter a participant starts on a new study medication.

An ophthalmoscopic exam to evaluate for the pres-ence of cataracts is conducted as part of the screeningphysical exam. Followup ophthalmoscopic exams are con-ducted every 6 months and at end-of-phase visits.

Statistical Methods and Analytic Plan

The statistical methods and analytic plan of the CATIEschizophrenia trial are described in detail by Davis et al. else-where in this issue. They are briefly summarized below.

Primary Outcome—Phase 1. The primary analysis willconsist of a comparison of treatment discontinuation ratesbetween the conventional treatment group and the pooledatypical treatment groups in phase 1 from the beginningof the trial (olanzapine, quetiapine, risperidone).Treatment discontinuation will be defined as withdrawalfrom randomized treatment or the study itself for any rea-son, including lack of safety, lack of efficacy, poor med-ication adherence, or patient decision (after clinical rea-soning and discussion with the patient by the clinicianhave taken place). The analysis will be conducted on theintent-to-treat population, with success or failure definedfor all patients randomized. The objective is to determineif the atypical treatments maintain patients on their origi-nal therapy for a longer period than the conventional ther-apy. To this end, Kaplan-Meier estimates of the time totreatment discontinuation will be produced. Hypothesistests for assessing treatment differences will be based onthe Wilcoxon rank test for differences in survival distribu-tions (Kalbfleisch and Prentice 1980) between the pooledatypical treatments and the conventional treatment, adjust-ing for baseline status (exacerbated, partially remitted)and clinical site. Once daily and BID dose groups will bepooled for all primary analyses.

In the second step of the primary analysis, the threeatypical treatment groups will be compared. Assuming asignificant difference was found between the pooled atypi-cals and the conventional in phase 1, comparisons for timeto all-cause treatment discontinuation will be made amongthe three atypical treatment groups for phases 1 and 1Acombined to determine if any treatments are substantiallydifferent from the others.

All other analyses of the primary outcome or analysesof secondary outcomes will be considered descriptive innature, and statistical significance will therefore be evalu-ated relative to p = 0.05 as a descriptive tool.

Secondary analyses of the primary outcome, control-ling for baseline covariates, will be performed using pro-portional hazards regression models (Cox 1972). In partic-ular, an analysis of treatment discontinuation adjusted forclinical site, baseline status, and whether the patient is ran-domized to a QD or BID treatment regimen will be con-ducted, and any interaction between baseline status or reg-imen and treatment will be assessed. Other covariates ofinterest will include baseline demographic variables (e.g.,gender) and overall disease severity. Interactions betweensignificant covariates and treatment effects will beassessed in the context of the proportional hazards models.

Primary Outcome—Phase 2. Patients are eligible toreceive rerandomization to an atypical treatment (to whichthey had not previously been assigned) if their originallyassigned atypical treatment fails. Because the second

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stage treatment is randomly assigned among atypicaltreatment arms, the study design will support treatmentcomparisons based on this rerandomization. However,because patients and investigators will choose betweentwo different trials in phase 2, data from these two trialswill not be combined for statistical comparisons. Withineach trial, analyses will be conducted with respect toselected outcomes in order to compare the performance ofthe different treatment groups as second lines of treat-ment. In particular, an analysis of time from re-random-ization to all-cause treatment discontinuation will be con-ducted using survival analysis techniques as describedabove. The primary analysis will focus on two mainhypotheses:

• Comparison of ziprasidone versus olanzapine,quetiapine, and risperidone combined in the trialfor patients who discontinued the first random-ized treatment because of tolerability issues

• Comparison of clozapine versus olanzapine, que-tiapine, and risperidone combined in the trial forpatients who discontinued the first randomizedtreatment because of lack of efficacy

Analyses will be performed using similar methodolo-gies as those described for the first phase.

Other Outcomes. Initial analyses of all secondary out-come variables will be based on the phase 1 and 1A treat-ment randomization in an intent-to-treat fashion, regard-less of the treatment the patient is receiving at the end ofthe study. The goal of this approach is to assess whichtreatment is superior as initial therapy regardless of anysubsequent randomizations.

Human Subjects Considerations

Given the heightened public and scientific concern aboutthe participation of mentally ill subjects in research, aCATTE Ethics Committee, chaired by Paul Appelbaum,M.D., was established to review all human subjects con-siderations. This committee reviewed the protocol and rec-ommended the procedures outlined below.

Assessment of Decisional Capacity. All prospectiveresearch participants are screened for decisional capacityusing the MacArthur Competence AssessmentTool-Clinical Research (MacCAT-CR) (Appelbaum andGrisso 1996). Persons who demonstrate adequate deci-sional capacity to participate in this research study areallowed to decide whether to enter the study. Those whochoose to participate sign a consent form and enter thescreening phase.

Persons who are initially assessed not to have thecapacity to make an informed decision but who wish toparticipate are offered a brief structured educational pro-gram based on the one used by Carpenter et al. (2000). Theprogram focuses on the prospective participant's difficul-ties in learning and manipulating information in an effortto improve the person's level of functioning to the pointwhere a competent decision can be made about whether toenter the study. After this program is completed, decisionalcapacity is again assessed using the MacCAT-CR. Personswho demonstrate decisional capacity at that time sign aconsent form and enter the screening phase of the study.

Persons who are determined not to have the capacityto consent to participate in a research study even afterremediation are not enrolled in the study unless a guardianis available and guardian consent for research is allowed inthe particular study site's jurisdiction.

To assess decisional capacity longitudinally, and toexamine the effects of the study medications on decisionalcapacity, the MacCAT-CR is administered to participantsat screening, month 6, month 18, and each end-of-phasevisit. The screening, month 6, and month 18 administra-tions coincide with neurocognitive assessments.

Informed Consent and Subject Advocate Procedures.Consent is obtained at the outset for all phases of thestudy except for the followup phase. (Consent for the fol-lowup phase is obtained at the time of entry into thatphase.) All participants are asked to appoint a person whoserves as a "subject advocate," who is involved with theinformed consent discussion and assists the subject withdecision making. Optimally, the subject advocate is a per-son of the patient's choosing—usually a family memberor close friend. In the event that such a person is not avail-able, each research site designates a person not otherwiseinvolved with the research project (e.g., a social worker, acase manager) to serve in this role. If at any subsequentpoint the participant is believed to have severely impairedcapacities to protect his or her own interests, then the sub-ject advocate makes a decision as to whether the patientshould leave the study. That determination is based onwhether there has been such a substantial decrement inthe benefit-risk ratio for this participant that the assump-tions on which the participant's original decision to enterthe study were predicated are no longer valid.Involvement by the subject advocate is ongoing but isespecially important at entry into phases 2 and 3.

Summary

This article has described the rationale, aims, and designof the CATTE schizophrenia trial; its procedures; and its

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proposed method of evaluating the effectiveness ofantipsychotic medications in the broad population ofpatients with schizophrenia who are treated clinically withthem. The protocol represents a type of pragmatic trial thatis intended to evaluate the effectiveness of treatments inthe settings where they are used for the purpose of generat-ing results that benefit clinicians, administrators, policymakers, and patients. In the context of clinical therapeuticsand interventions research, such studies provide an impor-tant bridge for the verification and translation of findingsfrom traditional randomized controlled trials to clinicalpractice and public mental health care.

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Acknowledgments

This article was based on results from the ClinicalAntipsychotic Trials of Intervention Effectiveness(CATTE) project supported with Federal funds from theNational Institute of Mental Health (NIMH) under con-tract NO1 MH90001. The aim of this project is to examinethe comparative effectiveness of antipsychotic drugs inconditions for which their use is clinically indicated,including schizophrenia and Alzheimer's disease. Theproject was carried out by principal investigators from theUniversity of North Carolina, Duke University, the Uni-versity of Southern California, the University ofRochester, and Yale University in association with Quin-tiles, Inc., and the program staff of the Division of Inter-ventions and Services Research of the NIMH and investi-gators from 84 sites in the United States. AstraZenecaPharmaceuticals LP, Bristol-Myers Squibb Company, For-est Pharmaceuticals, Inc., Janssen Pharmaceutica Prod-ucts, L.P., Eli Lilly and Company, Otsuka PharmaceuticalCo., Ltd., Pfizer Inc., and Zenith Goldline Pharmaceuti-cals, Inc., provided medications for the studies.

The Authors

T. Scott Stroup, M.D., M.P.H., is Associate Professor,Department of Psychiatry, University of North Carolina

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School of Medicine, Chapel Hill, NC. Joseph P. McEvoy,M.D., is Associate Professor, Department of Psychiatry,Duke University, Durham, NC; and Deputy ClinicalDirector, John Umstead Hospital, Butner, NC. Marvin S.Swartz, M.D., is Professor, Department of Psychiatry andBehavioral Science, Duke University, Durham, NC.Matthew Byerly, M.D., is Assistant Professor of Psychia-try, The University of Texas Southwestern Medical Cen-ter at Dallas, TX. Ira Glick, M.D., is Professor, Depart-ment of Psychiatry and Behavioral Science, StanfordUniversity School of Medicine, Stanford, CA. JoseCanive, M.D., is Director, Psychiatry Research, NewMexico VA Health Care System, and Associate Professorof Psychiatry, University of New Mexico, Albuquerque,NM. Mark McGee, M.D., is Chief Clinical Officer ofAppalachian Behavioral Healthcare, and Assistant Pro-fessor of Psychiatry, Department of Specialty Medicine,Ohio University College of Osteopathic Medicine,Athens, OH. George Simpson, M.D., is Professor ofResearch Psychiatry and Interim Chair, Department ofPsychiatry, University of Southern California KeckSchool of Medicine, Los Angeles, CA. Michael Stevens,M.D., is Medical Director, Valley Mental Health, and

Director, Psychopharmacology Research Unit, ValleyMental Health, Salt Lake City, UT. Jeffrey A. Lieberman,M.D., is Thad and Alice Eure Professor of Psychiatry,Pharmacology, and Radiology and Vice-Chairman ofPsychiatry, University of North Carolina School of Med-icine, Chapel Hill, NC.

Drs. Stroup and McEvoy are Co-Principal Investiga-tors (Pis) of the CATIE schizophrenia trial. Dr. Liebermanis PI of the CATTE project and of the schizophrenia trial.Dr. Swartz is Co-PI of the CATTE Clinical and FunctionalAssessment Unit. Drs. Byerly, Glick, Canive, McGee,Simpson, and Stevens are the site Pis who have recruitedthe largest number of study subjects at the time of publica-tion and have made significant contributions to the study.

•For the Schizophrenia Trial Center Members: C.E.Davis, Ph.D.; Kenneth Davis, M.D.; Sonia Davis, DrPH;Susan Essock, Ph.D.; Don Goff, M.D.; John Hsiao, M.D.;Richard Keefe, Ph.D.; Gary Koch, Ph.D.; Barry Lebowitz,Ph.D.; Jeffrey Lieberman, M.D.; Steve Marder, M.D.;Joseph McEvoy, M.D.; Herbert Meltzer, M.D.; AlecMiller, M.D.; Del Miller, M.D.; Diana Perkins, M.D.,MPH; Robert Rosenheck, M.D.; Nina Schooler, Ph.D.;Marvin Swartz, M.D.

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