CAFE Study Full Protocol

8/7/2019 CAFE Study Full Protocol

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Trial Number: 50771L/0114Date of Approval: October 12, 2001Revision 1: August 05, 2002:':Revision 2:.March 01,2003

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Jeffrey A. Lieberman, MDDiana O. Perkins, MD, MPHJoseph McEvoy, MD .Hongbin .Gu PhDRobert Hamer Ph0Gary Koch Ph0

This document is a confidential communication of AstraZeneca Pharmaceuticals LP (AstraZeneca).Acceptance of this document constitutes the agreement by the recipient that no unpublishedinformation contained herein will be published or disclosed without the prior written approval ofAstraZeneca, except that this document may be disclosed to appropriate Institutional Review Boardsso long as they are requested to keep it confidential.


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-,Efficacy and Tolerability of O/anzapine, Quetiapine and Rispen'done in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison .

1. BACKGROUND AND RATJONALE .................................................................. 52. SPECIFICAIMS 72.1. OVERVlEW 72.2. PRIMARY AIM 72.3. SECONDARY AIMS ; , 7

3. STUDY DESIGN "' "' ~.. II 93.1. OVERVIEW 9 .3.2. RATIONALE FOR STUDY DeSIGN, DOSES AND CONTROL GROUPS 93.2.1. Phase 1 S f

';3 .2 .2 . . .Phase 2 ; hMt: ..g ,: elir rfin ? :c k _ c! .... .... 9lISlt Intervals .

3.2.4. Enrollment 103.3. SELECTION OF STUDY POPULATION 103.3.1. study Selection Record .~ 103.3.2. Inclusion Criteria 103.3.3. Exclusion Criteria: 103.3.4. Discontinuation of Subjects from Treatmentor Assessment.. 113.3.4.1. Criteria for Discontinuation , 113.3.4.2. Voluntary Discontinuation by a Subject 123.4. TREATMENTS ~ 123.4.1. Investigational Products 123.4.1.1. Drug Packaging & Labeling Design 123.4.1.2. Storage and Inventory Management.. 133.4.1.3. Accountability 13

3.4.2. Dosesand Treatment Regimens 133.4.2.1. Dosing and Administration 13 .3.4.2.2. Discussion of Dosing Design 143.4.2.3. Concomitant and Adjunctive Medication 153.4.3. Method of Assigning Subjects to Treatment Groups 153.4.4. Blinding and Procedures for Unblinding the Study 163.4.4.1. Methods for Insuring Blinding 163.4.4.2. Methods for Unblinding the Study 16

4. STUDY MEASUREMENTS AND ENDPOINTS 174.1. SAFETi MEASUREMENTS AND ENDPOINTS 174.1.1. Adverse Events :~ 17

. 4.1.1.1. Definitions , 174.1.1.2. Serious Adverse Events ~ 174.1.1.3. Oeath 184.1.1.4. Recording of Adverse Events 194.1.1.5. Reporting of Serious Adverse Events 194.2. MEASURES OF ASSESSMENT 20

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Efficacy and Tolerabilify of OJanzapine, Quetiapine and Rispetidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison

4.2. 1. . Rationale for Assessment Measures 204.2.1.1. Clinical Assessments: ,.204.2.1.2. Other Clinical Outcomes 224.2.1.3. Neurocognitive Function (120 minute battery) 22

4.2.2. Quality Control ofClinical and Functional Assessments 235. STATISTICAL ANALYSES: 24

5.1. INTRODUCTION 245.2. STUDY OBJECTIVES AND ENDPOINTS 245.2.1. Study Objectives 245.2.2. Primary Objective 245.2.3. Secondary Objectives 245.2.4. Study Endpoints and Evaluations 245.3. ANALYSIS POPULATIONS AND DATASETS 255.3. 1. Definitions of Analysis Populations 255.3.2. Application of Analysis Populations " 265.3.3. . Definition of Analysis Datasets 265.3.4. Application of the Analysis Data sets 26

5.4. DATA QUALITY AND ASSURANCE 265.5. STATISTICAL CONSIDERATIONS 265 .5 . 1 . General Statistical Procedures 265.5.2. Patient Enrollment and Disposition 265.5.3. Protocol Deviations 275.5.4. Analysis ofDemographic and Other Baseline Characteristics 275.5.4.1. Patient Demographics 275.5.4.2. General Medical and Psychiatric History 27

5.6. ANALYSIS OF EFFECTIVENESS DATA : 275.6.1. Primary Effectiveness Parameter 275.6.2. Pooling of Small Centers for Ana/ysis 275.6.3. Analysis of Primary Effectiveness Parameter 275.6.3.1. Covariate Adjustment 28 .5.6.3.2. Subgroup Ana/yses 295.6.3.3. Missing Data Considerations 295.6.3.4. Secondary Effectiveness Parameters 295.6.3.5. Pooling of Small Centers for Analysis 295.7. ANALYSIS OF SAFETY' DATA : 30

5.7.1. Adverse Events 305.7.2. Deaths and Other Serious Adverse Events 305. 7.3. Vital Signs 305.7.4. Laboratory Parameters ' 305.8. SAMPLE SIZE DETERMINATION 30

6. NUMBER OF SITES AND RATE OF ENROLLMENT 31

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7. APPENDICES 327.1. (ApPENDIX A) FURTHER GUIDANCE ON THE DEFINITION OF AN SAE 32


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Efficacy and Tolerability of O/anzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison

1. Background and RationaleSchizophrenia is a serious, often disabling and recurrent'mental i llness. Previously, theprognosis of patients with schizophrenia was thought to be poor and the disease associatedwith an inexorably progressive course (McGlashan, 1988). However, studies of first episodepatients early in their course of illness have demonstrated their superior treatment response(in comparison to chronic multi-episode patients) and ability to achieve symptomaticremission and good outcomes with the proper treatment (Lieberman et aI., 1993; Robinsonet al., 1999). In general first episode patients show enhanced sensitivity to both thetherapeutic and side effects of treatment.The advent of a new generation of "atypical" antipsychotics, including olanzapine, quetiapineand risperidone, has improved the potential for decreasing the morbidity and disabilityassociated with schizophrenia. While the atypical antipsychotics have certainpharmacological properties in common (notably 5HT2AlC and 02 antagonism), there areimportant pharmacological differences with potential relevance for both safety and efficacy(Kinon & Lieberman, 1996). There are 17 published clinical trials comparing atypical withtypical antipsychotics primarily in patients with chronic schizophrenia or schizoaffectivedisorder. These studies have predominantly included patients with longstanding and chronicillness, and generally report improved tolerability and comparable or improved efficacy ofatypical over typical medications (Arvanitis & Miller, 1997; Beasley et al., 1997; Peuskens &Link, 1997; Small et aI., 1997; Tollefson et al., 1997; Beasley Tollefson, et aI., 1996;Beasley, Sanger, et al., 1996; Slin, Azorin & Souhours, 1996; Sorison, Arvanitis & Miller,1996; Fabre et al., 1995; Peuskens, 1995; Marder & Meibach, 1994; Ceskova & Svestka,1993; Chouinard et al., 1993; Hoyberg et al., 1993; Min et aI., 1993; Claus et al., 1992).Little is known about the comparable efficacy and safety of the atypical antipsychotics,however, since few head to head double-blind comparisons trials have been completed andonly in chronic patients. One published study reports a double-blind comparison ofolanzapine with risperidone in 339 patients with schizophrenia, finding that the twomedications produced roughly comparable symptom reduction but a higher proportion ofpatients responded to olanzapine, and olanzapine caused fewer EPS and sexual side. effects (Tran et. al., 1997). A second study of both drugs found them comparably effective(although risperidone showed slight superiority on some symptom dimensions) and nodifferent on EPS rates (Conley and Mahmoud, 2001). In both studies olanzapine exhibitedgreater weight gain. An open label 4-month study comparing quetiapine with risperidone in751 patients with psychosis found similar improvement in positive and negative symptoms,but significantly greater improvement in depressive symptoms in quetiapine versusrisperidone treated patients (Borison, Arvanitis & Miller, 1997). In this study quetiapine was

/ better tolerated as evidenced by decreased incidence of substantial EPS.I t S G e l ' ) I~Page 5


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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week ComparisonIt has been proposed that atypical antipsychotic medication should be used preferentially inthe treatment of first episode patients with psychotic disorders (Lieberman 1996). Firstepisode patients are an important population and in many ways ideal subjects to study thecomparative benefits and tolerability of the atypical antipsychotics. First episode patientsare a highly treatment responsive group, and may be best able to realize the full benefits ofa drug. In addition, first episode patients are sensitive to side effects, especiallyextrapyramidal and weight gain side effects (Sanger et al., 1999). Thus, differences intolerability may be highlighted in this patient population. They require lower doses onaverage than more chronic patients do. In addition, they will not have had lengthy priorexposure to antipsychotic medication treatment, and thus prior treatment effects do notconfound differences in tolerability and treatment responsivity. It may be that clinicalbenefits of atypical antipsychotics will best be demonstrated in this more homogeneous andpristine patient population. There are preliminary data that are consistent with this premise.A sub-analysis of a 1,996 subject olanzapine clinical trial data base, where a group of 83first-episode patients were identified (Sanger et aI., 1999). suggested that olanzapinetreated patients showed significantly greater improvements in the Brief Psychiatric RatingScale (BPRS) total and negative scores and in the Positive and Negative Syndrome Scale(PAN,SS) total and positive scores compared to the patients treated with haloperidol. Inaddition, a greater proportion of olanzapine treated patients (67%) compared withhaloperidol treated patients (29%) were rated as "clinically improved" by the end of theshort-term trials (>40% reduction in the BPRS). The olanzapine treated patientsexperienced significantly less EPS than haloperidol treated patients. In addition, there havebeen several studies (either recently completed or still in progress) that have examined thecomparative efficacy of the atypical drugs olanzapine and risperidone with each other andwith conventional anti psychotics in first episode patients. However, there has been no studyinitiated to examine the comparative effects of quetiapine to the other atypical drugs. Thereare several reasons to believe that quetiapine may be an effective drug for treating patientswith first episode psychosis. First, quetiapine has the lowest EPS liability of anyantipsychotic drug. First episode patients are extremely sensitive to these effects and havea very high incidence (>70% with conventional drug treatment). Second, first episodepatients are highly susceptible to weight gain associated with atypical antipsychotic therapy.Weight gain is particularly problematic in first episode patients as they are bothered by thecosmetic aspects of weight increases, and since they are likely to be on medication foryears to come, are vulnerable to the medical consequences of the weight gain. Third, firstepisode patients require lower doses of medication to achieve therapeutic responses.Consequently, the wider dose range of quetiapine and the fact that it is currently being used

, at doses on the lower half of the therapeutic range will not be as much of a disadvantage intreating first episode patients. All of these factors contribute to patients' potential adherenceto treatment. The issue of treatment adherence is of critical importance in first episodeIR 8a20 1;S Page 6


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Efficacy and Tolerability of O/anzapine. Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparisonpatients. Recent studies have shown that although these patients respond very well(achieving 1 year remission rates of >80%) the 1-year attrition rates are as high as 60%. Asignificant cause of nonadherence is side effects and tolerability of medications.

2. Specific Aims2.1. OverviewThe purpose of this study is to compare the effectiveness, tolerability, and efficacy of theatypical antipsychotic drugs olanzapine (2.5-20 mg/day ) , quetiapine (100-800 mg/day) andrisperidone (0.5-4 mg/day) in patients with schizophrenia, schizophreniform disorder, or .schizoaffective disorder experiencing their first psychotic episode. The study design is arandomized, double-blind, parallel and symmetrical 3-arm 52 week clinical trial.2.2. Primary Aim .The primary aim of this trial is to evaluate the effectiveness of olanzapine, quetiapine, andrisperidone in the treatment of the first episode of psychosis. T h e primary outcome variableto evaluate effectiveness is "all cause pharmacologic treatment discontinuation," as reflectedby the proportion of patients that discontinue from the study prior to 52 weeks of treatment.This outcome measure was chosen due to its high clinical relevance and the fact that itintegrates both tolerability and efficacy. The primary hypothesis is two-fold: that quetiapineis non-inferior to risperidone, and that quetiapine is non-inferior to olanzapine, in the rates ofall cause pharmacologic treatment discontinuation.

2.3. Secondary AimsThe secondary aims of this trial are:a) To evaluate the effectiveness of olanzapine, quetiapine, and risperidone in the

treatment of the first episode of psychosis by comparing the time to "all-causepharmacologic treatment discontinuation."

b) To examine the efficacy of olanzapine, quetiapine, and risperidone in treatingsymptoms of schizophrenia, as follows:1. Effects on total symptoms, and on positive, negative, mood, insight into illness

(ITAQ) and SUbstance use symptoms at 12,24 and 52 weeks (or LOCF) oftreatment, as measured by change from baseline in PANSS total score, positiveand negative sub-scales, the Calgary Depression Rating Scale, and substanceuse (AUSIDUS).

2. Effects on neurocognition (attention, memory, executive function, socialcognition) at 12 and 52 weeks (or LOCF), as measured by change from baseline.J

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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 5 2 Week Comparison

3. The proportion of individuals that are remitted (defined as no item on the PANSS> 3 and CGI rated ~mildly ill" or less).

4. Time to illness remission.5; Proportion of subjects that end study participation due to lack of efficacy prior to

52 weeks of treatment.6. Quality of life (QOL) and service utilization outcomes at 12, 24 and 52 weeks (or

LOCF).c) To compare the tolerability of olanzapine, quetiapine, and risperidone in first episode

patients as indicated by:1. Risk of akathisia (Barnes global score >2), Parkinsonian symptoms (Simpson

Angus total score> .3), and clinically significant EPS (indicated by treatment withbenztropine, lorazepam or propranolol for treatment of medication side effects atany time prior to the evaluation time point) at 12, 24 and 52 weeks (or LOCF) oftreatment.

2. Proportion of subjects that end study participation due to intolerance prior to 52weeks of treatment.

3. .Proportion of subjects that have a clinically significant increase in weight(increase in 8M! of 3 or more points) and proportion of subjects that are obese(8MI > 30) at 12, 24, and 52 weeks of treatment.

4. Mean change in fasting cholesterol, triglycerides, HgA1c and glucose at 12, 24and 52 weeks (or LOCF) of treatment.5. Mean change in prolactin, estrogen or testosterone level and proportion of

subjects with sexual adverse effects at 12 and 52 weeks (or LOCF) of treatment.6. Change (baseline to highest value) " o f : akathisia (Barnes Akathisia Scale),

Parkinsonism (Simpson-Angus Rating Scale), weight gain and frequency ofadverse events at 12,24 and 52 weeks (or LOCF) of treatment.

7. Overall adherence to treatment at 12, 24 and 52 weeks (or LOCF). Adherence isdefined on a 4-point likert scale, rated after a structured clinical interview (pleasesee Source Document for details, adherence is rated as: 1=always/almostalways, 76-100% of the time; 2=Usually, 51-75% of the time; 3=Sometimes, 26-50% of the time; 4=Never/Almost never, 0-25% of the time).

)

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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychoSis: A Randomized Double Blind 52 Week Comparison

. Phase 2: V6-9 11-17 days 14 daysPhase 2: V10-19 25-31 days 28 daysL/ ' /Y! I r l C J e / / P h i . L i " 3 . .: .If2-0- : 2 . 3

3.2.4. EnrollmentAn informed consent document approved by an ethical review board or similar body will besigned by the patient or the patient's authorized legal representative prior to the patient'sparticipation in this study.3.3. Selection of Study Papulation3.3.1. Study Selection RecordThe study subjects will be recruited from patients who present to inpatient, outpatient, oremergency room services for the evaluation and treatment of psychosis. Study subjectsmay also be ascertained. through media advertising, at the discretion of the site principalinvestigator with the approval of the sponsor (AstraZeneca) and the IRS.

5.

3.3.2. Inclusion Criteria1. Meets DSM IV criteria for

schizoaffective disorder.2. Has no previous history

antipsychotic medication3. Between 16-40 years of4. Psychotic symptoms

than 5 years (60 months).

guardian able to p rTlrln~TI6. Female patients of child

means of contraception.7. Score on at least one PANSS psychosis items (P1, P2, P3, PS, or P6) ~ 4 and

CGI Severity score :::4 (moderate) at point of maximum severity of illness todate.

3.3.3. Exclusion Criteria:1. Past history of any DSM-IV psychotic disorder with recovery. Recovery is

defined as a period of at least 3 months with no active positive symptoms.2. Patients with heavy co-morbid substance use, where the presenting psychotic.

symptoms are judged by the study physician as likely to be substance induced.Page 10


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Efficacy and Tolerability of Ofanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison

3. Female patients who are either pregnant or nursing.4. Known history of mental retardation.S. Non-english speaking (mastery of English insufficient to participate in study

evaluation procedures).6. Serious, unstable medical illness.7. Known allergy to any study medication.8. At serious suicidal risk.9. Participation in clinical trial of an investigational drug within 30 days of visit 1.

3.3.4. Discontinuation of Subjects from Treatment or Assessment

3.3.4.1. Criteria for DiscontinuationPatients may be withdrawn from the trial for any of the following reasons:1. Inadequate therapeutic effect (requiring alternative treatment). (Note: subjects shall

not be withdrawn due to lack of efficacy if the maximum dose has not been achieved;except lf the patient is not having adequate response but higher doses are nottolerated, then this can be considered as a discontinuation for lack of efficacy.)

2. Unacceptable side effects3. Patient decision (examples include but are not limited to):

a. Withdrawal of informed consent.b. Subject lost to foHow-up (dropouts).

4. Administrative (examples include but are not limited to):a. Site protocol noncompliance (protocol violations or deviations).b. Other independent external events that preclude further participation in the

protocol for a subject who would otherwise continue (e.q. moving, accidentaldeath, pregnancy).

The reason for withdrawal must be documented on the CRF provided. If a subject iswithdrawn due to an adverse event, then the adverse event must be specified on the CRFprovided. If a subject is withdrawn all assessments that are specified for the end of the trialperiod should be carried out wherever possible. All withdrawals due to serious AEs must bereported to Quintiles' Safety Surveillance and Reporting office within 1 day. Withdrawals

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Etticecyenti To{erability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparisondue to the occurrence of non-serious AEsmust be reported to Quintiles'Safety Surveillanceand Reporting office within 15 days.Any subject who withdraws during th e trial and has clinically significant or abnormal findingson any safety assessment will have a follow-up visit within 1 week and at appropriateintervals thereafter until the abnormality resolves. Where possible, patients should befollowed up for 30 days after the last dose of trial drug is given. All deaths and all seriousAEs should be reported to Quintiles' Safety Surveillance and Reporting office. On-going. .AE's should be followed up until resolved or stabilized .

3.3.4.2. . Voluntary Discontinuation by a SubjectSubjects. are free to discontinue their participation in the study at any time, without prejudiceto further treatment. Subjects who discontinue from the study' should be asked about thereason(s) for their discontinuation and about the presence of any adverse events, I fpossible, they should be seen and assessed by aninvestlqatorts), Adverse events shouldbe followed up and the subject should return all investigational products.3.4. Treatments3.4.1. Investigational ProductsThe following drugs are used in this trial: Quetiapine (Seroquel) distributed by AstraZeneca, Inc., supplied by the sponsor in

dosage of 100 mg. Risperidone distributed by Janssen Pharmaceutica lnc., purchased by the sponsor in

dosage of 0.5 mg. Olanzapine distributed by Ully Inc., purchased by the sponsor in dosage of 2.5 mg.Capsule strengths are listed below:

Olanzapine 2.5 mgQuetiapine 100 mgRisperidone 0.5 mg

3.4.1.1. Drug Packaging & Labeling DesignOver-encapsulated study drug capsules will be filled into high-density polyethylene bottles, .which will be capped using child resistant closures with induction inner seals. Each bottlewill contain one-hundred twenty-four (124) capsules.

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efficacy and Tolerability of Olanzapine. Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Compadson3.4.1.2. Storage and Inventory ManagementAll product will be monitored in a secure, limited access area at controlled roomtemperature.Quintiles will be responsible for monitoring study drug inventory atdistribution center when to shbelow its re-order point, thenrespective target level}.The Quintiles interactive voistudy drug replacement boxesThe Quintiles IVR system willexpired 60 days prior to the

and notifying theat the site falls

prevent a subject fromSpecific procedures for using thManual to be distributed at site

nce

3.4.1.3.The investigator, his/her designee or a hospital pharmacist must maintain an adequaterecord of the receipt and distribution of all trial supplies using the Drug Accountability Form.These forms must be available for inspection at any time. Trial drug prescription, dispensingand compliance will be captured on the case report forms and will be source validated byQuintiles monitors.

3.4.2. Doses and Treatment Regimens3.4.2.1. Dosing and AdministrationAll subjects will begin with one capsule (olanzapine 2.5 mg, quetiapine 100mg, risperidone.5 mg). During the first 6 weeks of treatment, medication may be increased by one capsuleat the discretion of the clinician with a minimal period between dose increases of 48 hours.Dose increases should be made based on clinical response and tolerability, arrd it isrecommended that the length of the dosing intervals be increased if the subject experiencesmedication side effects. The recommended initial target dose is 2 study pills BID (e.g;BID of olanzapine, 200 BID quetiapine, or 1 mg BID of risperidone). The maximum dose is8 capsules a day administered in a BID schedule. BID dosing must be maintained, and it isrecommended (but not required) that the larger dose be given in the evening when the splitdoses are not equal. Dose decreases may be at any time and at any dosing increment atthe discretion of the study clinician.

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Efficacy and Tolerability of O/anzapine, Quetiapine and Risperidone in the Treatment ofFj[~t EpisodePsychosis: A Randomized Double Blind 52 Week Comparison '. ""In many cases the subject will enter the study on antipsychotic treatment. Here, the clinicianmay chose to simultaneously decrease the prior antipsychotic and increase the studyantipsychotic (e.g. cross-titrate the medications). Less frequently, the clinician may chose toabruptly stop the prior antipsychotic and initiate the study antipsychotic. The studyphysician should use his or her best clinical judgment when making decisions abouttransition from prior antipsychotic to the study antipsychotic.The following initial dosing schedule is recommended, but the clinician should individualizetreatment in each subject based on tolerability and clinical response:

3 . 4 . 2 . 2 . Discussion of Dosing DesignThe dosing range was chosen to allow clinicians maximal flexibiHty in dosing eachantipsychotic medication in first episode patients. The dosing range takes into the accountthat first episode patients, compared to patients with chronic schizophrenia, usuaJly respondto lower doses of antipsychotic medication, and will be more likely to develop adverse. effects if the highest dose range of the antipsychotic medication is used. The starting dosefor the study antipsychotic is at the lower end of the therapeutic range in order to minimizethe risk of adverse effects. The titration schedule is also chosen to minimize the risk ofacute adverse effects, and to maximize initial tolerability of each medication. A more rapidtitration rate could inflate discontinuation rates due to acute adverse effects, and thuspotentially bias study results.The rationale for BID dosing relates to the fact that quetiapine needs to be administeredBID, although risperidone and olanzapine may be administered once a day. In order tomaintain the study blind, it will be necessary to administer all drugs twice daily. Otheroptions (e.g. a mosaic design) would result in at least a partial break of the blind. The. disadvantage of the BID dosing is that previous studies have shown that medicationadherence is enhanced with once daily versus more frequent medication dosing. Thus, the

. potential advantage of a once a day drug ver~us twice a day drug on all-causepharmacologic treatment discontinuation will not be assessed in this study; In summary, theadvantage of different dosing schedules for the three drugs is substantially outweighed bythe disadvantage posed by breaking the study blind.

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Efficacy and Tolerabl1ity of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison3.4.2.3. Ccncomltant and Adjunctive Medication

i. Extrapyramidal side effects: Concomitant medication will be allowed for a limitedtime period of 2 weeks to treat emergent extrapyramidal side effects. Concomitantmedication for extrapyramidal side effects will not be allowed for a cumulative totalof more than 1 4 days over the course of-the trial. Clinicians are encouraged torespond to emergent EPS by reducing the dose of the study antipsychoticmedication. Benzodiazepine treatment for akathisia is included in this 14-day limit(but benzodiazepine use is not restricted for symptoms of anxiety or agitation.) Therationale for this strategy I S that each of the antipsychotic medications included Inthis trial is reported to have an efficacious dose that is lower than the threshold dosethat will induce EPS. Thus, clinicians will be encouraged to lower the dose ofantipsychotic medication if EPS emerges. If the treating clinician determines thatshort-term EPS medication is needed to control the acute emergence of EP8, thenbenztropine will be allowed to treat Parkinsonian or dystonic symptoms, andpropranolol or lorazepam to treat akathisia.

Ii. Co-morbid disorders and symptoms: Other antipsychotic medications will be allowedonly in those subjects who enter the study on an antipsychotic, and the clinicianjudges that cross-titration of old and study antipsychotic is Clinically indicated. Otherantipsychotics will not be allowed for treatment of agitation, anxiety, residualpsychosis, or for any other reason. Antidepressants and mood stabilizers will not beallowed during the first 8 weeks of the trial to minimize the risk that individuals withprimary mood disorders might be included in the protocol. After 8weeks clinicianswill be allowed to treat co-morbid Axis Idisorders as clinically indicated. Clinicianswill be allowed to treat co-morbid anxiety/agitation/insomnia as needed at any timeduring the study, with any appropriate medication (except that other antipsychoticmedications are not allowed). Except as noted in this section, there are norestrictions on use of concomitant or adjunctive medications.

3.4.3. Method of Assigning Subjects to Treatment GroupsSubject eligibility will be established before treatment randomization. Subjects will berandomized by Quintiles IVR system to provide centralized randomization services duringPhases 2. If a subject discontinues from the study, the subject number will not be reused,and the subject will not be allowed to re-enter the study. The Quintiles lVR system willrandomize subjects into one of three treatment arms during Phase 2:

I/

olanzapine (2.5-20 mg/day)quetiapine (100-800 mg/day)

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Efficacy and Tolerability of O/anzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparisonrisperidone IEach bottle will be labeled with an 10 number specific double blind label. Subjects will beassigned to an initial treatment kit during Phase 2 and re-supplied with additional treatmentkits at each study visit. When a subject discontinues or completes the trial, all unusedstudy medication will be returned to the investigative site for accountability and destructionas described in the Study Reference Manual.

3.4.4. Blinding andProceduresfor Unblindingthe Study3.4.4.1. Methodsfor Insuring BlindingThis study aims to adhere to the principles of research design and conduct that ensure theintegrity of studies and the validity of data derived from them. Laska and colleagues (1992)have written that, "As an abiding principle, ReTs designed for hypothesis testing shouldstrive for the most rigorous blinding procedures possible in order to minimize the risk o fcompromising the study's integrity, which inevitably leads to uncertainties about the validityof inferences. This furthers the interest of the global community in enabling valid decisionmaking. ~There is an obligation to all patients who participate in this study and to all thosewhose treatment will be influenced by the results of this study to implement the study insuch a way that it produces valid results (i.e., a close approximation of truth).3.4.4.2. Methods for Unbtindingthe StudyWe also have a responsibility to individual patients participating in this study and to theirtreating clinicians to provide information from this study that will maximally inform treatmentdecisions. However, if we adopted a policy of providing unblinded information to all patientsafter their completion of this study we could jeopardize the results of this study.Therefore, we have adopted a policy in which unblinded information will be provided only inthose situations wherein the need for this information is substantial, that there is significantclinical risk to the patient should unblinding not occur. The unblinding information will begiven only to medical care providers that are not affiliated with this study. _Excepting medicalemergency, at no time should any investigator or staff member associated with the study beunblinded. The policy requires application to the Study Trial Center, initiated by contact withthe project Medical Office, by patients or their treating clinicians. Such situations mayinclude, but are not limited to:

L When a patient has dropped out orbeen withdrawn from the study and there is aconcern for the patient's well being due to a serious adverse event that has placedthe patient at grave medical risk.

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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparisoni i . When there is a desire to maintain a patient who has had an exceptionally favorable

therapeutic outcome (e.g., if a patient has completed Phase2).Sites that strongly desire to unblind the treatment of a patient who has had a favorableoutcome should send a brief (one-page) letter to Dr. Lieberman stating:a) the specifics of the case that justifies unblinding and why they believe this option is

important enough so thatthe individual patient's needs warrant risking the study'sintegrity;

b} the name and contact information of the treating clinician who will receive the unblindedtreatment information;

c} how the site intends to restrict access to the unblinded information to only thoseclinicians who will care for a patient after completion of that patient's participation in thestudy, and restrict thls information and any follow-up on this patient from study researchstaff at the site.

4. STUDY MEASUREMENTS AND ENDPOINTS4.1. Safety Measurements and Endpoints4.1.1. Adverse Events4.1.1.1. DefinitionsThe definitions of adverse events (AEs), serious adverse events (SAE's) and othersignificant adverse events (OAE's) are given below. It is of the utmost importance that allstaff involved in the study is familiar with the content of this section. The principalinvestigator is responsible for ensuring this at each site.An adverse event is the development of an undesirable medica!" condition or thedeterioration of a pre-existing medical condition following or during exposure to apharmaceutical product, whether or not considered causally related to the product. Anundesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g.,tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratoryfindings, electrocardiogram). In clinical studies, an AE can include an undesirable medicalcondition occurring at any time, including run-in or wash-out periods even if no studytreatment has been administered.

4.1.1.2. Serious Adverse EventsThe trial period is defined from the time that the informed consent document is signed until30 days after administration of the last dose of the trial drug. All serious AEs occurringduring the trial period (including death due to any cause) or within 30 days after


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Efficacy and To/erability ofOfanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparisonadministration of the last dose of the trial drug must be communicated within 1 day of theinvestigator becoming aware of the event to the Quintiles' Safety Surveillance and Reportingoffice designated personnel, using the telephone or fax numbers provided in the StudyReference Manual. Any fatal or life threatening AEs must be reported to Quintiles' SafetySurveillance and Reporting office immediately, but no longer than 1 day from the time theinvestigator becomes aware of the event. A causality assessment must be provided for allserious AEs. Critical follow-up information on serious AEs must be provided as soon as it isavailable, but no longer than 1 day from the time the investigator became aware of theinformation. Other essential, but not critical, information may be reported within thefollowing 5 days. Although it is important to report all serious AEs to Quintiles' SafetySurveillance and Reporting office designated personnel within 1 day, extra measures mustbe taken to ensure that any serious, unexpected, possibly drug-related AE becommunicated immediately. AstraZeneca will be responsible for relaying appropriateinformation regarding serious AEs to the regulatory authorities.A serious AE is defined as one that satisfies any of the following criteria:

Results in death. Is immediately life-threatening, including potentially life threatening suicidal behavior

or suicidal behavior that results in hospitalization. Requires inpatient hospitalization or prolongation of existing hospitalization.

[Note: Hospitalization for symptoms related to schizophrenia, schizoaffectivedisorder, or schizophreniform disorder, such a s psychosis or mood symptoms are anexpected part of the disease and thus should not be recorded as a serious adverseevent, but should be recorded as an adverse event.] Results in persistent or significant disability or incapacity.

Is a congenital abnormality or birth defect.Is an important medical event that may jeopardize the subject or may require medical

intervention to prevent one of the outcomes listed above.For further guidance on the definition of an SAE, see Appendix A .The causality of SAE's (i.e., their relationship to study treatment) will be assessed by theinvestigator(s), who in completing the relevant case report form must answer "yes" or "no" tothe question "Do you consider that there is a reasonable possibility that the event may havebeen caused by the drugT For further guidan!=e on the definition of a SAE and a guide tothe interpretation of the causality question, see Appendix B.

4.1.1.3. DeathAll deaths occurring within the trial period or within 30 days after the last dose of trial drug isgiven must be reported to Quintiles' Safety Surveillance and Reporting office within 1 day.

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Efficacy and Tolerability of O/anzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Bfind 52 Week ComparisonIf the reason.for withdrawal from the trial is death, this event may be reported as a seriousAE. The cause of death should be documented on the appropriate CRF. An AE CRFshould be completed for all conditions except objective progression of disease, and theevent must be reported to Quintiles' Safety Surveillance and Reporting office as a seriousAE within 1 day. The report should contain information regarding the co-involvement ofprogression of disease, jf appropriate, and incorporate information regarding the primaryand secondary causes of death. If an autopsy has been performed, results of the autopsymust be obtained and forwarded to Quintiles' Safety Surveillance and Reporting office alongwith any available toxicology reports.

4.1.1.4. Recording of Adverse EventsIt is important to distinguish between serious and severe AE's. Severity is a measure ofintensity whereas seriousness is defined by the criteria in Section 4.4.2.1 b). An AE ofsevere intensity need not necessarily be considered serious. For example, nausea thatpersists for several hours may be considered severe nausea, but not a SAE. On the otherhand, a stroke that results in only a limited degree of disability may be considered a mildstroke, but would be an SAE.Should a pregnancy occur it must be reported in accordance with the procedures describedbelow. Pregnancy in itself is not regarded as an AE unless there is a suspicion that aninvestigational product may have interfered with the effectiveness of a contraceptive..medication. However, the outcome of all pregnancies (spontaneous miscarriage, electivetermination, normal birth or congenital abnormality) must be followed up and documentedeven if the subject was discontinued from the study.All reports of congenital abnormalities/birth defects are SAE's. Spontaneous miscarriagesshould also be reported and handled as SAE's. Elective abortions without complicationsshould not be handled as AE's. All outcomes of pregnancy must be reported to Quintiles onthe pregnancy outcomes report form.

4.1.1.5. Reporting of Serious Adverse EventsThe process flow for reporting serious adverse events along with associated documents andcontactinformation will be presented in the Study Reference Manual to accompany thisprotocol. The first report from the site of a se~ous adverse event will be made by phone andfollowed with facsimile (FAX). The investigator must provide the minimal information: l.e. trialnumber, subject's initials and date of birth, medication code number, period of intake, CRFI.D. number and nature of the adverse event and investigator's causality assessment. Thesites' point of contact for SAE reporting will be Quintiles Drug Safety Surveillance andReporting Office (contact information is provided in the Study Reference Manual). The sites


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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparisonwill also have the opportunity to make initial contact with the Project Medical Officer (PMO)also described in Study Reference Manual, for clarifying the event seriousness criteria.This report of a serious adverse event by telephone must always be confirmed by a written,more detailed report. For this purpose, the sites will,be provided with an AstraZenecaapproved SAE Form for Clinical Trials, to be completed and signed by the Investigator. If anon-serious case becomes serious, this and other relevant information should also beprovided to Ouintiles' Safety Surveillance and Reporting office within 1 day as described inthe paragraph above.After initial notification, the Safety Surveillance and Reporting office will inform AstraZenecadesignated personnel and the Project Medical Officer at UNC of the event. The Surveillanceand Reporting office will be responsible for collecting source documents and confirming theseriousness, relationship to study product and expectedness. Narratives created by theSafety Surveillance and Reporting office and all supporting documentation will be sent to thePMO for medical review and to the sponsor at the same time. The PMO will review andacknowledge receipt of the report to Quintiles. The PMO wiU review the SAE in a timelyfashion, and return the document to Quintiles if any changes are needed.Surveillance and Reporting office will handle any questions needing follow-up with the siteor the site monitor. Quintiles office will forward any follow-up information to AstraZeneca.AstraZeneca will file theSAE reports via Clintrace Reporting and will assume responsibilityfor any necessary expedited reporting of adverse events to the authorities with concurrentnotification to Quintiles and the investigators. It is the investigator's responsibility to reportthe AE's which are classified by the sponsor as serious, unlisted and associated with theuse of the drug to the Independent Ethics Committee I Institutional Review Board (lEG/IRS)which has approved the protocol unless otherwise required and documented by thelECIlRB.All SAEs have to be reported, whether or not considered causally related to theinvestigational product. All SAEs will be recorded in the case report form. The investigator isres ponsible for infonning the Ethics Committee and/or the Regulatory Authority of the SAEas per local requirements.4.2. Measures of Assessment4.2.1. Rationale for Assessment Measures

)

4.2.1.1. Clinical Assessments:. The primary outcome measure, Mall-cause treatment discontinuation" is rated on the samemeasure developed for use in the CATIE trial. This rating form requires the clinician to datethe phase discontinuation, and then to indicate whether the discontinuation was

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Efficacy and Tolerability of O/anzapine, Queliapine and Rispetidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison"administrative" (e.g. the patient moved) or "cllnical." A "clinical" discontinuation is thenfurther rated as being either: 1} clinician decision inadequate therapeutic effect, 2) cliniciandecision unacceptable side effects, or 3) patient decision. Rating rules have beenestablished for each of these 3 categories, and all raters will be required to pass certificationin completing the ratings of "all-cause treatment discontinuation." Our experience with theCATIE trial indicates that a high level of reliability (kappa> .9) can be achieved andmaintained in the use of this scale with our training program.The clinical assessment tools, including the Positive and Negative Symptom Scale(PANSS). the Calgary Depressidn Rating Scale (CDRS). the Clinical Global Impressions(CGI). and the Alcohol Use Scale/Drug Use Scale (AUSIDUS), Symptom Onset inSchizophrenia (SOS) Scale, and the Structured Clinical Interview for DSMIV disorders haveestablished reliability and validity. These instruments assess important domains ofpsychopathology in patients with schizophrenia and related psychotic disorders. ThePANSS provides good coverage of positive, negative, and general psychopathology, butdoes not provide detailed information about mood symptoms. We included a more detailedassessment of mood symptoms(CDRS) due to the recognized importance of moodsymptoms in schizophrenia, and the potential for atypical anti psychotics to impact mood.The AUS/oUS are single item questionnaires that provide information about severity ofsubstance use problems. We included this domain to assess the interaction betweenadherence and severity of substance use.Adverse effects will be thoroughly assessed by patient interview, ratings on extrapyramidalrating scales (AIMS. BARS, SA), and laboratory studies. Weight will be assessed throughwaist hip measurement, and direct assessments of weight. Adverse effects will beevaluated both by general and systematic inquiry. Extrapyramidal side effects will beevaluated by physical exam. Laboratory studies will include fasting glucose and lipid panelsto evaluate impact of drugs on glucose tolerance and risk of hyperlipidemia. HemoglobinA 1c levels will be evaluated to further evaluate' glucose metabolism. Prolactin, estrogen andtestosterone will assess impact of drugs on these hormones. Other routine chemistries willbe systematically assessed as well to evaluate general health.Vital signs (systolic and diastolic blood pressure) will be measured at every visit up to andincluding week 12, week 24, week 52 and end of study.A physical exam at screening will include an ophthalmologic exam for the detection ofcataracts. This examination of the eyes will be repeated at six-month intervals and at theend of study.

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Efficacy and Tolerability of O/anzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison3.4.1.2. Storage and Inventory ManagementAll product will be monitored in a secure, limited access area at controlled roomtemperature.Quintiles will be responsible for monitoring study drug invdistribution center when to shbelow its re-order point, thenrespective target level).The Quintiles interactivestudy drug replacement boxesThe Quintiles IVR system willexpired 60 days prior to the

at the site falls .

r re-ordering

prevent a subject from receSpecific procedures for usingManual to be distributed at site

3.4.1.3.The investigator, his/her designee or a hospital pharmacist must maintain an adequaterecord of the receipt and distribution of all trial supplies using the Drug Accountability Form.These forms must be available for inspection at any time. Trial drug prescription, dispensingan d compliance will be captured on the case report forms and will be source validated byQuintiles monitors.

3.4.2. Doses and Treatment Regimens3.4.2.1. Dosing andAdministrationAll subjects will begin with one capsule (olanzapine 2.5 mg, quetiapine 100 mg, risperidone.5 mg). During the first 6 weeks of treatment, medication may be increased by one capsuleat the discretion of the clinician with a minimal period between dose increases of 48 hours.Dose increases should be made based on clinical response and tolerability, and it isrecommended that the length of the dosing intervals be increased if the subject experiencesmedication side effects. The recommended initial target dose is 2 study pills BID (e.q,BID of olanzapine, 200 810 quetfapine, or 1 mg BID of risperidone). The maximum dose is8 capsules a day administered in a BID schedule. BID dosing must be maintained, and it isrecommended (but not required) that the larger dose be given in the evening when the splitdoses are not equal. Dose decreases may be at any time and at any dosing increment atthe discretion of the study clinician. I I l & C Q Q I 51.' Page 13


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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of.fJ.'9t EpisodePsychosis: A Randomized Double Blind 52 Week Comparison .'- ...In many cases the subject will enter the study on antipsychotic treatment. Here, the clinicianmay chose to simultaneously decrease the prior antipsychotic and increase the studyantipsychotic (e.g. cross-titrate th e medications). Less frequently, the clinician may chose toabruptly stop the prior antipsychotic and initiate the study antipsychotic. The studyphysician should use his or her best clinical judgment when making decisions abouttransition from prior antipsychotic to the study antipsychotic.The following initial dosing schedule is recommended, but the clinician should individualizetreatment in each subject based on tolerability and clinical response:

3 . 4 . 2 . 2 . Discussion of Dosing DesignThe dosing range was chosen to allow clinicians maximal flexibiHty in dosing eachantipsychotic medication in first episode patients. The dosing range takes into the accountthat first episode patients, compared to patients with chronic schizophrenia, usually respondto lower doses of antipsychotic medication, and will be more likely to develop adverseeffects if the highest dose range of the antipsychotic medication is used. The starting dosefor the study antipsychotic is at the lower end of the therapeutic range in order to minimizethe risk of adverse effects. The titration schedule is also chosen to minimize the risk ofacute adverse effects, and to maximize initial tolerability of each medication. A more rapidtitration rate could inflate discontinuation rates due to acute adverse effects, and thuspotentially bias study results.The rationale for BID dosing relates to the fact that quetiapine needs to be administeredBID, although risperidone and olanzapine may be administered once a day. In order tomaintain the study blind, it will be necessary ~oadminister all drugs twice daily. Otheroptions (e.g. a mosaic design) would result in at least a partial break of the blind. Thedisadvantage of the BID dosing is that previous studies have shown that medicationadherence is enhanced with once daily versus more frequent medication dosing. Thus, thepotential advantage of a once a day drug ve~us twice a day drug on all-causepharmacologic treatment discontinuation will not be assessed in this study: In summary, theadvantage of different dosing schedules for the three drugs is substantially outweighed bythe disadvantage posed by breaking the study blind .

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Efficacy and Tolerability of O/anzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison 3.4.2.3. concornttant and Adjunctive Medicationi. Extrapyramidal side effects: Concomitant medication will be allowed for a limitedtime period of 2 weeks to treat emergent extrapyramidal side effects. Concomitant

medication for extrapyramidal side effects will not be allowed for a cumulative totalof more than 14 days over the course ofthe trial. Clinicians are encouraqedtorespond to emergent EPS by reducing the dose of the study antipsychoticmedication. Benzodiazepine treatment for akathisia is included in this 14-day limit(but benzodiazepine use is not restricted for symptoms of anxiety or agitation.) Therationale for this strategy is that each of the antipsychotic medications included inthis trial is reported to have an efficacious dose that is lower than the threshold dosethat will induce EPS. Thus, clinicians will be encouraged to lower the dose ofantipsychotic medication if EPS emerges. If the treating clinician determines thatshort-term EPS medication is needed to control the acute emergence of EPS, thenbenztropine will be allowed to treat Parkinsonian or dystonic symptoms, andpropranolol or lorazepam to treat akathisia.

ii. Co-morbid disorders and symptoms: Other antipsychotic medications will be allowedonly in those subjects who enter the study on an antipsychotic, and the clinicianjudges that cross-titration of old and study antipsychotic is clinically indicated. Otherantipsychotics will not be allowed for treatment of agitation, anxiety, residualpsychosis, or for any other reason. Antidepressants and mood stabilizers will not beallowed during the first 8 weeks of the trial to minimize the risk that individuals withprimary mood disorders might be included in the protocol. After 8 weeks clinicianswill be allowed to treat co-morbid Axis I disorders as clinically indicated. Clinicianswill be allowed to treat co-morbid anxiety/agitation/insomnia as needed at any timeduring the study, with any appropriate medication (except that other antipsychoticmedications are not allowed). Except as noted in this section, there are norestrictions on use of concomitant or adjunctive medications.

3.4.3. Method of Assigning Subjects to Treatment GroupsSubject eligibility will be established before treatment randomization. Subjects will berandomized by Quintiles IVR system to provide centralized randomization services duringPhases 2. If a subject discontinues from the study, the subject number will not be reused,and the subject will not be allowed to re-enter the study. The Quintiles IVR system willrandomize subjects into one of three treatment arms during Phase 2:olanzapine (2.5-20 mg/day)quetiapine (100-800 mg/day)

Pagets


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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison

risperidone tEach bottle will be labeled with an 10 number specific double blind label. Subjects will beassigned to an initial treatment kit during Phase 2 and re-supplied with additional treatmentkits at each study visit. When a subject discontinues or completes the trial, all unusedstudy medication will be returned to the investigative site for accountability and destructionas described in the Study Reference Manual.

3.4.4. BHnding and Procedures for Unblinding the Study3.4.4.1. Methods for Insuring BlindingThis study aims to adhere to the principles of research design and conduct that ensure theintegrity of studies and the validity of data derived from them. Laska and colleagues (1992)have written that, ~As an abiding principle, RCTs designed for hypothesis testing shouldstrive for the most rigorous blinding procedures possible in order to minimize the risk ofcompromising the study's integrity, which inevitably leads to uncertainties about the validityof inferences. This furthers the interest of the global community in enabling valid decisionrnakinq." There is an obligation to all patients who participate in this study and to all thosewhose treatment will be influenced by the results of this study to implement the study insuch a way that it produces validresults (i.e., a close approximation of truth).3.4.4.2. Methods for Unblinding the StudyWe also have a responsibility to individual patients participating in this study and to theirtreating clinicians to provide information from this study that will maximally inform treatmentdecisions. However, if we adopted a policy of providing unblinded information to all patientsafter their completion of this study we could jeopardize the results of this study.Therefore, we have adopted a policy in which unblinded information will be provided only inthose situations wherein the need for this information is substantial, that there is significantclinical risk to the patient should unblinding not occur. The unblinding information will begiven only to medical care providers that are not affiliated with this study .. Excepting medicalemergency, at no time should any investigator or staff member associated with the study beunblinded. The policy requires application to the Study Trial Center, initiated by contact withthe project Medical Office, by patients or their treating clinicians. Such situations mayinclude, but are not limited to:

/.

L When a patient has dropped out or been withdrawn from the study and there is aconcern for the patient's well being due to a serious adverse event that has placedthe patient at grave medical risk .

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Efficacy and Tolerability of Olanzapine. Quetlapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison

ii. When there is a desire to maintain a patient who has had an exceptionally favorabletherapeutic outcome (e.g., if a patient has completed Phase 2).

Sites that strongly desire to unblind the treatment of a patient who has had a favorableoutcome should send a brief (one-page) letter to Dr. Lieberman stating:a) the specifics of the case that justifies unblinding and why they believe this option is

important enough so that the individual patient's needs warrant risking the study'sintegrity;

b) the name and contact information of the treating clinician who will receive the unblindedtreatment information;

c) how the site intends to restrict access to the unblinded information to only thoseclinicians who will care for a patient after completion of that patient's participation in thestudy, and restrict this information and any follow-up on this patient from study researchstaff at the site.

4. STUDY MEASUREMENTS AND ENDPOINTS4.1. Safety Measurements and Endpoints4.1.1. Adverse Events4.1.1.1. DefinitionsThe definitions of adverse events (AEs), serious adverse events (SAE's) and othersignificant adverse events (OAE's) are given below. It is ofthe utmost importance that allstaff involved in the study is familiar with the content of this section. The principalinvestigator is responsible for ensuring this at each site.An adverse event is the development of an undesirable medical condition or thedeterioration of a pre-existing medical condition following or during exposure to apharmaceutical product, whether or not considered causally related to the product. Anundesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g.,tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratoryfindings, electrocardiogram). In clinical studies, an AE can include an undesirable medicalcondition occurring at any time, including run..in or wash-out periods even if no studytreatment has been administered.

4.1.1.2. Serious Adverse EventsThe trial period is defined from the time that the informed consent document is signed until30 days after administration of the last dose of the trial drug. All serious AEs occurringduring the trial period (including death due to any cause) or within 30 days after


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./

Efficacy and To/erability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison .administration of the last dose of the trial drug must be communicated within 1 day of theinvestigator becoming aware of the event to the Quintiles' Safety Surveillance and Reportingoffice designated personnel, using the telephone or fax numbers provided in the StudyReference Manual. Any fatal or life threatening AEs must be reported to Quintiles' SafetySurveillance and Reporting office immediately, but no longer than 1 day from the time theinvestigator becomes aware of the event. A causality assessment must be provided for allserious AEs. Critical follow-up information on serious AEs must be provided as soon as it isavailable, but no longer than 1 day from the time the investigator became aware of theinformation. Other essential, but not critical, information may be reported within thefollowing 5 days. Although it is important to report all serious AEs to Quintiles' SafetySurveillance and Reporting office designated personnel within 1 day, extra measures mustbe taken to ensure that any serious, unexpected, possibly drug-related AE becommunicated immediately. AstraZeneca will be responsible for relaying appropriateinformation regarding serious AEs to the regulatory authorities.A serious AE is defined as one that satisfies any of the following criteria:

Results in death. Is immediately life-threatening, including potentially life threatening suicidal behavior

or suicidal behavior that results in hospitalization. Requires inpatient hospitalization or prolongation of existing hospitalization ..

[Note: Hospitalization for symptoms related to schizophrenia, schizoaffectivedisorder.or schizophreniform disorder, such as psychosis or mood symptoms are anexpected part of the disease and thus should not be recorded as a serious adverseevent, but should be recorded as an adverse event.] Results in persistent or significant disability or incapacity. Is a congenital abnormality or birth defect. Is an important medical event that may jeopardize the subject or may require medical

intervention to prevent one of the outcomes listed above.For further guidance on the definition of an SAE, see Appendix A .The causality of SAE's (i.e., their relationship to study treatment) will be assessed by theinvestigator(s), who in completing the relevant case report form must answer "yes or uno" tothe question "Do you consider that there is a reasonable possibility that the event may havebeen caused by the drug?" For further guidange on the definition of a SAE and a guide tothe interpretation of the causality question, see Appendix 8.

4.1.1.3. DeathAll deaths occurring within the trial period or within 30 days after the last dose of trial drug isgiven must be reported to Quintiles' Safety Surveillance and Reporting office within 1day .

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Efficacy and To/erabilityof Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison

If the reason .for withdrawal from the trial is death, this event may be reported as a seriousAE. The cause of death should be documented on the appropriate CRF. An AE CRFshould be completed for all conditions except objective progression of disease, and theevent must be reported to Quintiles' Safety Surveillance and Reporting office as a seriousAE within 1 day. The report should contain information regarding the co-involvement ofprogression of disease, if appropriate, and incorporate information regarding the primaryand secondary causes of death. If an autopsy has been performed, results of the autopsymust be obtained and forwarded to QuintHes' Safety Surveillance and Reporting office alongwith any available toxicology reports.

4.1.1.4. Recording of Adverse EventsIt is important to distinguish between serious and severe AE's. Severity is a measure ofintensity whereas seriousness is defined by the criteria in Section 4.4.2.1 b). An AE ofsevere intensity need not necessarily be considered serious. For example, nausea thatpersists for several hours may be considered severe nausea, but not a SAE. On the otherhand, a stroke that results in only a limited degree of disability may be considered a mildstroke, but would be an SAE.Should a pregnancy occur it must be reported in accordance with the procedures describedbelow. Pregnancy in itself is not regarded as an"AE unless there is a suspicion that aninvestigational product may have interfered with the effectiveness of a contraceptivemedication. However, the outcome of all pregnancies (spontaneous miscarriage, electivetermination, normal birth or congenital abnormality) must be followed up and documentedeven if the subject was discontinued from the study.All reports of congenital abnormalities/birth defects are SAE's. Spontaneous miscarriagesshould also be reported and handled as SAE's. Elective abortions without complicationsshould not be handled as AE's. All outcomes of pregnancy must be reported to Quintiles onthe pregnancy outcomes report form.

4.1.1.5. Reporting of Serious Adverse EventsThe process flow for reporting serious adverse events along with associated documents andcontact information will be presented in the Study Reference Manual to accompany thisprotocol. The first report from the site of a serious adverse event will be made by phone andfollowed with facsimile (FAX). The investigator must provide the minimal information: i.e. trialnumber, subject's initials and date of birth, medication code number, period of intake, CRF1.0. number and nature of the adverse event and investigator's causality assessment. Thesites' point of contact for SAE reporting will be Quintiles Drug Safety Surveillance andReporting Office (contact information is provided in the Study Reference Manual). The sites

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Efficacy and Tolerability of Ofanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparisonwill also have the opportunity to make initial contact with the Project Medical Officer (PMO)also described in Study Reference Manual, for clarifying the event seriousness criteria.This report of a serious adverse event by telephone must always be confirmed by a written,more detailed report. For this purpose, the sites will, be provided with an AstraZenecaapproved SAE Form for Clinical Trials, to be completed and signed by the Investigator. If anon-serious case becomesserious, this and other relevant information should also beprovided to Quintiles' Safety Surveillance and Reporting office within 1 day as described inthe paragraph above.After initial notification, the Safety Surveillance and Reporting office will inform AstraZenecadesignated personnel and the Project Medical Officer at UNC of the event. The Surveillanceand Reporting office will be responsible for collecting source documents and confirming theseriousness, relationship to study product and expectedness. Narratives created by theSafety Surveillance and Reporting office and all supporting documentation wiU be sent to thePMO for medical review and to the sponsor at the same time. The PMO will review andacknowledge receipt of the report to Quintiles. The PMO wiU review the SAE in a timelyfashion, and return the document to Quintiles if any changes are needed.Surveillance and Reporting office will handle any questions needing follow-up with the siteor the site monitor. Quintiles office will forward any follow-up information to AstraZeneca.AstraZeneca will file the SAE reports via Clintrace Reporting and will assume responsibilityfor any necessary expedited reporting of adverse events to the authorities with concurrentnotification to Quintiles and the investigators. It is the investigator's responsibility to reportthe AE's which are classified by the sponsor as serious, unlisted and associated with theuse of the drug to the Independent Ethics Committee I Institutional Review Board (IEC/IRS)which has approved the protocol unless otherwise required and documented by theIECIlRS.All SAEs have to be reported, whether or not considered causally related to theinvestigational product. All SAEs will be recorded in the case report form. The investigator isresponsible for informing the Ethics Committee and/or the Regulatory Authority of the SAEas per local requirements.4.2. Measures of Assessment4.2.1. Rationale for Assessment Measures4.2.1.1. Clinical Assessments:The primary outcome measure, Mall-cause treatment discontinuatlon" is rated on the samemeasure developed for use in the CATIE trial. This rating form requires the clinician to datethe phase discontinuation, and then to indicate whether the discontinuation was

I f t & O O O IsrPage 20...._---_._---


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Efficacy and Tolerability of O/anzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison"administrative" (e.g. the patient moved) or "clinical: A "clinical" discontinuation is thenfurther rated as being either: 1 ) clinician decision inadequate therapeutic effect. 2 ) cliniciandecision unacceptable side effects, or 3) patient decision. Rating rules have beenestablished for each of these 3 categories, and all raters will be required to pass certificationin completing the ratings of "all-cause treatment discontinuation.' Our experience with theCATIE trial indicates that a high level of reliability (kappa> .9) can be achieved andmaintained in the use of this scale with our training program.The clinical assessment tools, including the Positive and Negative Symptom Scale(PANSS), the Calgary Depression Rating Scale (CDRS), the Clinical Global Impressions(CGI), and the Alcohol Use Scale/Drug Use Scale (AUSIDUS), Symptom Onset inSchizophrenia (SOS) Scale, and the Structured Clinical Interview for DSMIV disorders haveestablished reliability and validity. These instruments assess important domains ofpsychopathology in patients with schizophrenia and related psychotic disorders. ThePANSS provides good coverage of positive, negative, and general psychopathology, butdoes not provide detailed information about mood symptoms. We included a more detailedassessment of mood symptoms (CDRS) due to the recognized importance of moodsymptoms in schizophrenia, and the potential for atypical anti psychotics to impact mood.The AUS/DUS are single item questionnaires that provide information about severity ofsubstance use problems. We included this domain to assess the interaction between

:'

adherence and severity of substance use.Adverse effects will be thoroughly assessed by patient interview, ratings on extrapyramidalrating scales (AIMS, BARS, SA), and laboratory studies. Weight will be assessed throughwaist hip measurement, and direct assessments of weight. Adverse effects will beevaluated both by general and systematic inquiry. Extrapyramidal side effects will beevaluated by physical exam. Laboratory studies will include fasting glucose and lipid panelsto evaluate impact of drugs on glucose tolerance and risk of hyperlipidemia. HemoglobinA 1c levels will be evaluated to further evaluate glucose metabolism. Prolactin, estrogen andtestosterone will assess impact of drugs on these hormones. Other routine chemistries willbe systematically assessed as well to evaluate general health.Vital signs (systolic and diastolic blood pressure) will be measured at every visit up to andincluding week 12, week 24, week 52 and end of study.A physical exam at screening will include an ophthalmologic exam for the detection ofcataracts. This examination of the eyes will be repeated at six-month intervals and at theend of study .

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Efficacy and Tolerability of O/anzapine, Quetiapine and Rispetioone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison4.2.1.2. Other Clinical OutcomesAspects of social and occupational functioning will be evaluated with the Heinrichs-Carpenter Quality of Life Scale (QOL). We wilt examine impact of insight as measured bythe Insight into Treatment and Attitudes Questionnaire (ITAQ) on treatment adherence.

4.2.1.3. Neurocognitive Function (120minute battery)

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schizophrenia. In contrast to assessment of patients with schizophrenia, cognitive function inpatients with dementia is usually assessed with one of several widely-available cognitivequestionnaires (e.g., Mini Mental Status Examination, Dementia Rating Scale, Alzheimer'sDisease Assessment Scale). These questionnaires can be easily administered at thepatient's bedside and are routinely employed in the screening of progressive neurologicaldisorders. The administration of these tests can help shed light on the global severity o f thecognitive deficits that the patient exhibits, track progression, and measure symptomchanges. The Brief Assessment of Cognition in Schizophrenia (BACS) is a brief clinicianadministered neurocognitive battery (30 minutes); The BACS will be administered in thisstudy to evaluate the usefulness of this brief battery in first episode schizophrenia. Theavailability of a quick and efficient tool for measuring the cognitive profile of a patient withschizophrenia will be an extremely useful guide to the clinician making decisions about thepotential rehabilitation of the schizophrenic patient. Further, this tool may be used to assessefficiently and effectively the extent to which cognitive deficits improve in the course oftreatment with novel antipsychotic medication.

4 . 2 . 2 . Quality Control of Clinical and Functional AssessmentsEffort spent at minimizing measurement error is rewarded by increase in study power(Blackwelder, 1982). In designing the training program for the clinical and functionalassessments, we considered both burden on the sites, and the potential gain in reliability ofratings. There will be a web based training program for all clinical and functionalassessments developed and maintained by the UNC coordinating team. An initial trainingwill be done at the study initiation meeting. Clinical and functional raters who do not attendthe study initiation meeting will receive their training based on completion of the web basedtraining program, supplemented with telephone meetings.For key outcomes, specifically "all-cause pharmacologic treatment discontinuation," thePANSS, and for the SCID (used to determine study eligibility) raters will participate incertification procedures. Certification for Mall-cause pharmacologic treatmentdisconttnuation" will use case vignettes, and certification will be given when a raterdemonstrates excellent (kappa>.9) agreement with the gold standard ratings. Similarly,certification for the SCID will use SCtD based case vignettes, and require good agreement(kappa> .8) with the gold standard ratings. Certification for the PANSS will involve rating 3video-taped interviews, and obtaining a passing score (lCC>.7). Raters who do not initiallypass certification will be offered remedial training and an opportunity to re-take thecertification evaluation. In addition, additional training will be offered during the course ofthe study during monthly telephone conferences.We will require maintenance training on these key outcome measures, in order to minimizethe risk of interviewer drift. The intensity of the maintenance training is based on the

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Efficacy and Tolerability of Ofanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparisondifficulty of scale, and the risk of interviewer drift. For both the SCIO and for "all-causetreatment discontinuation" annual re-certification is adequate to maintain reliable ratings,For the PANSS, given the complexity of this scale, more frequent training is needed, andwith ratings of PANSS tapes three times a year, and calculation of reliability (based on the 3tapes) annually.

5. Statistical Analyses:5.1. Introd uctionThis statistical analysis plan concentrates primarily on the analysis of effectiveness data,with a brief mention of safety data. A more elaborate statistical analysis plan (SAP) existsas a separate document.5.2. Study Objectives and Endpoints5.2.1. StudyObjectivesStudy objectives are to compare the three groups with respect to measures of effectiveness,safety, and tolerability .

5.2.2. Primary ObjectiveThe primary objective is to compare the effectiveness of quetiapine versus risperidone andolanzapine, on the primary response variable of "all-cause pharmacologic treatmentdiscontinuation." Each comparison (quetiapine versus risperidone, and quetiapine versusolanzapine) will be tested to show that quetiapine is not inferior to each respectivecomparator (Blackwelder 1982). For each subject, the primary response variable will bewhether that subject discontinued the study or study medication for any cause from phase 2of the trial prior to week 52.

5.2.3. Secondary ObjectivesThe secondary objectives are to compare the three groups with respect to other measuresof effectiveness, measures of tolerability, and measures of safety,

5.2.4. StudyEndpoints andEvaluationsAll-cause pharmacologic treatment discontinuation is a binary variable defined as follows:Any subject who has discontinued thetrial or study medication prior to week 52 will beconsidered to have met the criteria, Only those subjects who have stayed on studymedication through 52 weeks will be considered as having not met the criteria,Consequently, discontinuation includes events such as withdrawal due to adverse event,

I

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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparisonlost to follow-up, administrative reasons, and withdrawal due to non-efficacy. Note that thisprimary response variable is defined if} such a way that there can be no missing data.Secondary endpoints include reason for "all cause pharmacologi.cal discontinuation," changein psychopathology [measured with the total, positive, and negative symptom scales of thePositive and Negative Symptom Scale (PANSS)}. change in depressive symptoms[measured with the Calgary Depression Rating Scale (CDRS)], global psychopathology[measured with the Clinical Global Impression (CGI) scale), and substance abuse[measured with the Alcohol Use Scale IDrug Use Scale (AUSIDUS)].Analysis of safety measures will be covered later, but safety will be assessed using physicalexams, systematic ratings, laboratory studies, and assessment of adverse events (AEs).Laboratory measures will include fasting glucose and lipid panels, hemoglobinA 1c, prolactin,estrogen (women) or testosterone (men) and other routine blood chemistries.Neurocognitive function" will be assessed a battery of neurocognitive tests describedelsewhere in the protocol.The schedule of assessments and evaluations is given in section 3 of the protocol.

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4. Safety Cohort: The ITT population. The intention is to evaluate safety using allavailable data. It is possible that a subject might discontinue due to AE or SAEprior to the first post-randomization evaluation, and not return for furtherevaluations. For these subjects, the only safety responses available will bereported AE or SAE. For aUother safety evaluations, subjects need to be in theITT population to be evaluable for safety.

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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison5.3.2. Application of Analysis PopulationsThe ITT population will be used for evaluation of the primary effectiveness variable, all-cause pharmacologic treatment discontinuation, and for evaluation of AE or SAEinformation, where available. The MITT population will be used for all secondaryeffectiveness variables, including neurocognitive and social assessments, and for all safetyvariables. The evaluable cohort will be used for all effectiveness and safety evaluations ofbaseline to week 12 data. The safety cohort will be used for all safety analyses, exceptthose that can be done using the ITT population.

5.3.3. Definition of Analysis OatasetsTwo versions of the datasets will be used for many of ttiese analyses: an observed cases(OC) and a last observation carried forward (LOCF) dataset. Forthe primary effectivenessvariable, defined in a way that precludes missing data, there is no need to handle missingdata.

5.3.4. Application of the Analysis DatasetsEach dataset will include flags for each observation, for each occasion, indicating whetherthat observation is to be included in the ITT, MITT, Evaluable Cohort, or Safety Cohortdatasets. These flags will be used to select appropriate populations for analysis;

)5.4. Data Quality and AssuranceData entry, management, quality assurance, and quality control will be performed by theCRO, Quintiles Transnational.5.5. Statistical Considerations5.5.1. General Statistical ProceduresAl l analyses described in this protocol are a priori planned analyses. Other analyses will beexploratory, designed and run post hoc. All analyses will be designated as planned orexploratory in reports and articles. Unless stated otherwise, all statistical tests will be two-tailed tests using a significance level of 0.05, except possibly for tests used to makedecisions about covariates or blocking factors. In the event that some centers fail to enrollsufficient numbers of observations, small centers will be pooled together into analysiscenters using an algorithm described in sections 5.7.2 and 5.7.3.5.

5.5.2. Patient Enrollment and DispositionPatient disposition will be summarized by treatment group and by analysis population.Numbers and percentages of com pieters and dropouts will be listed, by treatment group andanalysis population. For all dropouts, the reason for dropout will be listed.

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Efficacy and Tolerability of Olanzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 52 Week Comparison Angioedema not severe enough to require intubation but requiring intravenoushydrocortisone treatment.

Hepatotoxicity caused by acetaminophen overdose requiring treatment with N-acetylcysteine.

Intensive treatment in an emergency room or at home for allergic bronchospasm. Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion) or

convulsions that do not result in hospitalization. Development of drug dependency or drug abuse.

Discontinuation of the trial treatment or of routine administration of prescription medications,or changes in their dosages should not be considered medical intervention.The fallowing information is the minimum that must be provided to Quintiles' SafetySurveillance and Reporting office within 24 hours for each serious event (see StudyReference Manual for fax and telephone numbers):

Trial number. Center number. Subject number. Subject initials. AE. Seriousness. Causality assessment. Date of onset. Study drug dose or amount.The following additional information must be provided to Quintiles' Safety Surveillance and

Reporting office as soon as it is available: Event intensity. Outcome (plus date of resolution if available) .. Withdrawal statement (yes or no). Concurrent therapy (identify treatment for AE). Date of birth and sex. Other current illnesses. Relevant medical history. Date and cause of death (if applicable).

Thisinformation should be captured on forms that AstraZeneca will provide. These formsshould then be faxed to Quintiles' Safety Surveillance and Reporting office.Should a serious AE be reported to an investigator at any time following the completion ordiscontinuation/withdrawal of a subject from the trial, inCluding any protocol required post-

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treatment follow-up, the investigator has an obligation to report the serious AE to Quintiles'Safety Surveillance and Reporting office if the investigator feels it is related to study drug.

7.2. (Appendix 8) A Guide to Interpreting the Causality QuestionThe following factors should be considered when deciding if there is a " re a s o n ab lepossibility" that anAE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the subject actually received thesuspect drug? Did the AE occur in a reasonable temporal relationship to theadministration of the suspect drug?

Ii Consistency with known drug profile. Was the AE consistent with the previousknowledge of the suspect drug (pharmacology and toxicology) or drugs of the samepharmacological class? OR could the AE be anticipated from its pharmacologicalproperties?

Dechallenge experience. Did the AE resolve or improve on stopping or reducing thedose ofthe suspect drug?

No alternative cause. The AE cannot be reasonably explained by another etiologysuch as the underlying disease, other drugs, other host or environmental factors.

Rechallenge experience. Did the AE reoccur if the suspected drug was reintroducedafter having been stopped? AstraZeneca would not normally recommend or supporta rechallenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed therelationship.

A "reasonable possibility" could be considered to exist for an AE where one or more of thesefactors exist.In contrast, there would not be a "reasonable possibility" of causality if none of the abovecriteria apply or where there is evidence of exposure and a reasonable time course but anydechallenge (if performed) is negative or ambiguous or there is another more likely cause ofthe AE.In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug? Is there a known mechanism?

Ambiguous cases should be considered as being a "reasonable possibility" of a causalrelationship unless further evidence becomes available to refute this. I B B O C X ) l w 7Page 34


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!:.i

Efficacy and Tolerability of O/anzapine, Quetiapine and Risperidone in the Treatment of First EpisodePsychosis: A Randomized Double Blind 5 2 Week Comparison7 . 3 . (Appendix C) Neurocognitive Assessment BatteryA battery of tests designed to assess treatment-related improvement should meet thefollowing criteria: reliability in patients with schizophrenia, statistical properties that allowsignificant improvement in most schizophrenic patients, and suggestions from previous datathat they may be responsive to specific atypical antipsychotic treatment (Davidson andKeefe, 1995; Keefe etal, 1999). The battery of tests proposed for this study will not onlymeet these criteria, but it will also include the tests that are the battery for theNeurocognitive Assessment Unit for the CATIE Project. This battery of tests was decidedupon by the CATIE Project's Neurocognitive Advisory Group.Despite the importance of cognitive deficits in the assessment and treatment ofschizophrenia, there are no easily administered cognitive scales to assess patients withschizophrenia. In contrast to assessment of patients with schizophrenia, cognitive functionin patients with dementia is usually assessed with one of several widely available cognitivequestionnaires (e.g., Mini Mental Status Examination, Dementia Rating

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