Seroquel Study 125 for Marketing Purposes

AZSER1721764

Seroquei study 125 D1441C00125 A 24-week, 24-we ek, Int Internati ernational, onal, Multicenter, pen-label, pen-label, Flexibie-dose, Flexibie-dose, R and andom om sed, Paral Pa rallel lel group, Phase IV Study to Compare the Effect on Glucose Metabolism of Quetiapine, Olanzapine and Risperidone

CSP v 1. 35 CDTpresentation IS Aug 2003 SRi

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AZSER1721765

5 Study Study Tea CST Data Programmer Abdul Aziz Al

CST Statistician Frank Miller

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Drug Safety, Susann Sus anna a Nlasmars Nlasmars

Serocjuef 5O77XL/0!25 -

CST/CSA Ann-Christin Selfn

CST Data Manager Anna-Katin Naslund

-

.-

Health Econo my / OR Sarah Harden Friberg,

CST Leader Sofia Rssberg

CSTCRA BkglUB KumUn Margareth® Heliborg

CRF-Dev&loper,

Eva C Arsdersson

IPS UK Karen Masheder CST Clinical Advssor Gdran Stenimg CSPv J.35CDT

18 Aug 2003 SRi

CST Consulting specialist Dr Newcomer Dr Peter Mfeson Dr Lett LfndstrSm













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Participating countries

• Czech Republic • • • • • • • • •

Denmark Finland Germany Norway Slovak Republic Unit Un ited ed Kingdom Romania Bulgaria South So uth Africa CSP

1.35

CDTpresentation 18 Aug2003 SR













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Study Study Background: •

Recently Recently much debate about metab oli olicc effects of atypicafs, and whether glucose dysregulation dysregulation and pro-diabetogenic effects are 'class effects.

•

Most evidence concerns concerns olanzapine and clozapine, but reports reports also on risperidone and queti quetiapine. apine.

•

Differential effects.on weight with atypical atypicalss have been reported. Definitely an issue for olanzapine. Link to diabetes.

•

During During 2001-2 003, several questionsrattacs" from health authorities on the weight/diabetes topic.

WE ARE LACKING GOOD M ETABOLI

ntation !8Aug ! 8Aug2G03 2G03SRi SRi C S P v I , 35 CDT presentation

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Purpose of he st study udy Regulatory purpose: Produce data that will help help us defend the Seroquel label. Commercial purpose: Produce data that will enable us to to generate commercially attractive and competitive essages n relation relation to to diabetes & w eight.

CSPv !.35CDTprssen !.35 CDTprssentation tationie ie Aug Aug 2003 2003 SRi













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>

Business objectives / claims

To demonstrate the superior safety / ttolerabiii olerabiiity ty p rofile rofile of S eroquel over olanzapine on glucose metabolism (and weight & lipids)

>

To provide long-term satey / tolerabiii tolerabiiity ty data on metabolism in patients with schizophrenia against comparators

>

To suppo rt regulatory defense on glucose disturbanc es observed in schizophrenic patients treated with atypical antipsychotics

+

To show comp arable effects effects on glucose and weight vs risperidone. risperidone.

+

To show comp arable safety / tolerabiiity tolerabiiity profile profile regarding regarding EPS vs-olanzapine, superior vs risperidone.

+

To show superior safety / tolerabiii tolerabiiity ty profil profile e on prolactin compa red to risperidone, comparable with olanzapine.

+

To show maintained eff effect ect (CGI) Seroquel (comparable to risperidone and olanzapine).

+

To obtain Quality of Lif Life e data data for Seroquel. CSP v 1,35 CDT presentation 18 Aug 2003 SRi















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Primary Objective To com pare the saf safety ety / tolerabiiit tolerabiiityy eff effect ect profile profile of quetiapine and olanzapine on glucose metabolism in schizophrenic patients.

Primary outcome variable. Evaluat ng the change from from baseline baseline to 24 wee ks, measured by Area Under the Curve (0-2h) (0-2h) of plasma pl asma glucose fol following lowing -0 ra Glucose Tolerance Test (OGTT).

CS

1.35 CDT presentation 18 Aug 2003 SRi













AZSER1721771

Secondary objectives (I) Glucose metabolism compare the safety / tolerabiiity profile of quetiapine and risperi risperidone done on giucose metabolism metabolism measu red by change from baseline baseline to week 24 in Area Under the Curve (0-2h) of plasma glucose foi foilowing lowing 2h - Oral Glucose Tolerance Test (OG TT). >T o further further com pare qu etiapine, etiapine, olanzapine and risperi risperidone done safet safetyy / tolerabiiity profile on glucose metabolism by evaluating: Plasma Plasma fasting-glucose fasting- glucose and insulin. insulin. Indexes of insulin sensitivity (ISI):

Incidence of patients with hyperglycemia. Incidence of patients with impaired fasting

AUC (r>2hXpiasn3a values of insuli followin followingg OGTT - = > ^

glucose or impaired glucose tolerance.

derived from OGTT according to fvlatsuda et a!.

Evaluation of explorative measures

Homeostasis model assessment JHOfv1A = fasting plasma insulin (mmol/L) "xTasting plasma glucose (uU/mL)/22.5) (uU/mL)/22.5)

®HbA1C • Plasma C»peptide level.













AZSER1721772

Secondary Objectives / Variables (II) To com pare the safet safetyy / tolerabiiity tolerabiiity profile quetiapine, oianzapin and risperidone from basel baseline ine to to week 24 on circumference Weight, BM and w aist circumference Lipid profile

cholesterol, HDL, LDL

-Efficacy. (CGI) • Prolactin level • Extra Pyramidal Syndrome (SAS* BA RS **, anticholinergic anticholinergic medication) • Adverse eve nts, blood p ressure, pulse pulse rate, EC • Patient rated QoL (PETIT scale***) • Com pliance pliance questionnaire (ROM!****) Simpson-Angus Scale; ** Barnes-Akathisia Scale; MfflSl&k

""""Personal Evaluation of Transitions in

Treatment;

**** Rating of Medical Influences Scale













AZSER1721773

Study Design

Population

• Sam ple size calculati calculation on based on weight as no data is available available on AUG and it's variance. • 600 screened, 570 random ised, 285 completed. • Randomisation will be stratified on BM and age usi using ng IVRS. • 5% drop-out is expected expected between screening an d rando misation, 50% drop-out during the 24 we eks. Inclusion. or outpatients with schizophrenia. • Male or female, 18-65 years years o ld. • Requiring Requiring a change in treatmen treatmen to tolerabiiity tolerabiiity or insuff insuffici icient ent efficacy. Exclusion. • Known diabetes diabetes or fast fasting ing plasma plasma glucose > 12 mg/dl. • Previous use of atypicals (3 (3 mo nths) or other m edications that might influence inf luence glucose me tabolism. tabolism.













AZSER1721774

Method for Primary Variable Oral Glucose Tolerance Test Patients to be 8-14h overnight fasted. No smoking allowe allowe d. - Req uires hos pitalization. n th morning, a venous catheter is put in place for determination of baseline plasma fasting glucose and insulin insulin co ncentrations. ncentrations. - The pa tient tient swallows 75 gr of liquid liquid glucose glucose (250-300 mi). - 4 bl blood ood samp les over 2 hours hours will will be drawn drawn (30, 90 and 12 minutes). Plasma g lucose and insulin insulin are analysed forcaluiation AUG. - Central laborator laboratoryy doing tthe he analysis: Covence

CSPv !.33CDTpresenlationl8Aiig20G3SRi















AZSER1721775

Investigational products • • • •

Open-label products C rosstitration rosstitration period for 5 days 23 weeks of treatment treatment w ith ith flexible dose Titration package and all quetiapine packed by IPS Comparators use of local commercial supplies













A2SER1721776

Study timetable Final protocol Investigat Invest igator or

Aug 15 2003 eetings

Dresden 19-21 Nov Montreaux 20-22 Jan

First First pati patient ent First First visit:

Novem ber 200

Recruitmen Recruitmentt pe period: riod:

12 months (Nov 2003 to Dec 2004)

Lastt pati Las patient ent Last is it:

July 2005













A2SER1721777

Potential issues • Setup Se tup f VRS time (delays?), cost. Comments from Ethics committees, Regulatory. • Slow recruit ent feasibility? Many patient already already on atypicals. Few patients suitable / willing to switch. - Hospitalizati Hospitalization on 3 + OGTT procedure.

Regulatory requests during the study time? • Budget -

600 patients, extensive labs, comparator drugs, IVRS













AZSER1721778

Study acronym

STAGE

- Schizophrenia Trial to evaluate Atypical antipsychotic Glucose Effects SEAHORSE - SEroquei AHead of Olanzapine and Risperidone in SafEty FATFARM

- Flexible dose Approach Trial For Atypical Atypic al Responses Responses to Metabolism POLARIS quetsaPine OLAnzapine Risperidone METEOR METabolism quetiapinE Olanzapine Risperidone EQUATOR-GM

-

Effect of Quetiapine, And That of Olanzapine and Risperidone on Glucos Metabolism?

MCGORS

study (after the famous Scottish McGors clan ).

Metabolic comparison of Glucose: Olanzapine, Risperidone and Seroqu^

SOLAR













AZSER1721779

international Principal appo po nted) Investigator not yet ap • Sug gestions from

Cs

- Dr olfgang Gaebel, Germany Dr Robin Efmsfey, South Africa DrHenrik Lublin, Denmark















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Inclusion Criteria













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Exclusion Criteria













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Exclusion Criteria













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Exclusion Exclusion criteria (III)













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Exclusion criteria (IV)















&ZSER1721785

2:

variables screeoinq and final visit at ee k 24 or discontinuation













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Laboratory analysis













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Statistical Methods (I) Populations for Analysis













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Statistical methods (II) Primary Analysis













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Statistical methods (III) Determination of sample size



























Seroquel Study 125 for Marketing Purposes

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