seroquel study 125 for marketing purposes

8/7/2019 Seroquel Study 125 for Marketing Purposes

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AZSER1721764

Seroquei study 125D1441C00125

A 24-week, International, Multicenter,Open-label, Flexibie-dose, Randomised, Parallel-group, Phase IV Study to

Compare the Effect on Glucose Metabolism ofQuetiapine, Olanzapine and Risperidone

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125 Study TeamDrug Safety,Susanna Nlasmars d

CST Data ProgrammerAbdul Aziz Al l

CST Data ManagerAnna-Katin Naslund CST Statist icianFrank Mil ler

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^ - - - _CST/CSAAnn-Christin Selfn

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Health Econo my / ORSarah Harden Friberg,CRF-Dev&loper,Eva C ArsderssonIPS / UKKaren MashederCST Clinical AdvssorGdran Stenimg

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Participating countries Czech Republic Denmark Finland Germany Norway Slovak Republic United Kingdom Romania Bulgaria South Africa

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Study Background: Recently much debate about metabolic effects of atypicafs, andwhether glucose dysregulation and pro-diabetogenic effects are'class1 effects. Most evidence concerns olanzapine and clozapine, but reports alsoon risperidone and quetiapine. Differential effects.on weight with atypicals have been reported.Definitely an issue for olanzapine. Link to diabetes. During 2001-2003, several questionsrattacs" from health authoritieson the weight/diabetes topic.WE ARE LACKING GOOD M ETABOLIC DATAI

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Purpose of the studyRegulatory purpose:Produce data that will help us defend theSeroquel label.Commerc ia l purpose:Produce data that will enable us to generatecommercially attractive and competitivemessages in relation to diabetes & w eight.

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Business objectives / claims> To demonstrate the superior safety / tolerabiiity p rofile of S eroquel overolanzapine on glucose metabolism (and weight & lipids)> To provide long-term satey / tolerabiiity data on metabolism in patients withschizophrenia against comparators> To suppo rt regulatory defense on glucose disturbanc es observed inschizophrenic patients treated with atypical antipsychotics

+ To show comp arable effects on glucose and weight vs risperidone.+ To show comp arable safety / tolerabiiity profile regarding EPS vs-olanzapine,

superior vs risperidone.+ To show superior safety / tolerabiiity profile on prolactin compa red torisperidone, comparable with olanzapine.+ To show maintained effect (CGI) Seroquel (comparable to risperidone andolanzapine).+ To obtain Quality of Life data for Seroquel. < s

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Primary ObjectiveTo compare the safety / tolerabiiity effect profile ofquetiapine and olanzapine on glucose metabolism inschizophrenic patients.

Primary outcome variable.Evaluating the change from baseline to 24 weeks,

measured by Area Under the Curve (0-2h) ofplasma glucose following 2h-0 ra lGlucose Tolerance Test (OGTT).CS V v 1.35 CDT presentation 18 Aug 2003 SRi


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Secondary objectives (I)Glucose metabolism>To compare the safety / tolerabiiity profile of quetiapine andrisperidone on giucose metabolism measured by change from baselineto week 24 in Area Under the Curve (0-2h) of plasma glucose foilowing2h - Oral Glucose Tolerance Test (OGTT).>T o further com pare quetiapine, olanzapine and risperidone safety /tolerabiiity profile on glucose metabolism by evaluating:Plasma fasting-glucose and insulin.Indexes of insulin sensitivity (ISI):* AUC (r>2hXpiasn3a values of insulinfollowing OGTT - = > ^M S | derived from OGTT according tofvlatsuda et a!.* Homeostasis model assessmentJHOfv1A = fasting plasma insulin (mmol/L)"xTasting plasma glucose (uU/mL)/22.5)

Incidence of patients with hyperglycemia.Incidence of patients with impaired fastingglucose or impaired glucose tolerance.Evaluation of explorative measuresHbA1C Plasma Cpeptide level.


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Secondary Objectives / Variables (II)To compare the safety / tolerabiiity profile of quetiapine, oianzapiand risperidone from baseline to week 24 onm Weight, BMI and waist circumference Lipid profile - cholesterol, HDL, LDL} TG-Efficacy. (CGI) Prolactin level Extra Pyramidal Syndrome (SAS*S BARS**, anticholinergic medication) Adverse events, blood p ressure, pulse rate, ECG Patient rated QoL (PETIT scale***) Com pliance questionnaire (ROM!****)* Simpson-Angus Scale; ** Barnes-Akathisia Scale;

MfflSl&k """"Personal Evaluation of Transitions in Treatment; **** Rating of Medical Influences ScaleW


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Study Design - Population Sample size calculation based on weight as no data is available onAUG and it's variance. 600 screened, 570 random ised, 285 completed. Randomisation will be stratified on BMI and age using IVRS. 5% drop-out is expected between screening and randomisation, 50%drop-out during the 24 weeks.Inclusion. ln or outpatients with schizophrenia. Male or female, 18-65 years o ld. Requiring a change in treatment due to tolerabiiity or insufficientefficacy.Exclusion. Known diabetes or fasting plasma glucose > 126 mg/dl. Previous use of atypicals (3 months) or other medications that mightinfluence glucose metabolism.


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Method for Primary VariableOral Glucose Tolerance Test- Patients to be 8-14h overnight fasted. No smoking allowe d.- Requires hospitalization.- In the morning, a venous catheter is put in place for determinationof baseline plasma fasting glucose and insulin concentrations.- The pa tient swallows 75 gr of liquid glucose (250-300 mi).- 4 blood samp les over 2 hours will be drawn (30, 60, 90 and 120

minutes). Plasma g lucose and insulin are analysed forcaluiation ofAUG.- Central laboratory doing the analysis: Covence

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Investigational products9 Open-label products C rosstitration period for 5 days 23 weeks of treatment w ith flexible dose Titration package and all quetiapine packed by IPS Comparators - use of local commercial supplies


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Potential issues Setup of IVRS - time (delays?), cost.@ Comments from Ethics committees, Regulatory. Slow recruitment / feasibility?

- Many patient already on atypicals.- Few patients suitable / willing to switch.- Hospitalization x 3 + OGTT procedure.

@ Regulatory requests during the study time? Budget- 600 patients, extensive labs, comparator drugs, IVRS

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Study acronymSTAGE- Schizophrenia Trial to evaluate Atypical antipsychotic Glucose Effects

SEAHORSE- SEroquei AHead of Olanzapine and Risperidone in SafEtyFATFARM- Flexible dose Approach Trial For Atypical Responses to Metabolism

POLARIS- quetsaPine OLAnzapine Risperidone

METEOR- METabolism quetiapinE Olanzapine Risperidone

EQUATOR-GM- Effect of Quetiapine, And That of Olanzapine and Risperidone on GlucoMetabolism?

MCGORS study (after the famous Scottish McGors clan ).- Metabolic comparison of Glucose: Olanzapine, Risperidone and Seroqu

SOLAR- Seroquel, OLanzapinef Risperdal ^ L

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international PrincipalInvestigator (not yet appointed) Suggestions from MCs

- Dr Wolfgang 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 criteria (III)

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Exclusion criteria (IV)


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Laboratory variables at screeoinq andfinal visit at w ee k 24 or discontinuation

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Statistical Methods (I)Populations for AnalysisAnalysis sets based on 3 patient populations: Safety population including all randomised patients who were g ivenstudy treatment classified according to the treatment they actuallyreceived. . The Intention To Treat population (ITT) will include all randomisedpatients who were given study treatment, classified according to thetreatment to which they were randomised The P rimary Analysis P opulation (PAP): all randomised patients whowere given study treatment and who have baseline and week 24assessments (+ 4 weeks) The per-protocol population (PP) excluding patients with significantprotocol violations or deviations and non-compliants from PAP.

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Statistical methods (II) PrimaryAnalysisAnalysis of covariance (ANCO VA): change from baseline in AUGplasma value of glucose following OGTT at week 24.independent va riables: baseline BM I group, age group, baseline AUGglucose m easurement and treatme ntLeast square means, p-values and 95% CI.The contrast of primary interest: the quetiapine-treated group and theolanzapine-treafed group.Mo p-vaiues for the other two contrasts.Center not included in the model (too large num ber of centers).

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Statistical methods (III)Determination of sample sizes No published data on the primary va riable and its variance. Powercalculation on change in weight since there is a fairly strongcorrelation between change In weight and change in plasma glucoselevels. Based on the number of patients needed to find a difference of 3 kg

in the m ean change from baseline to week 24 between thequetiapine- and the olanzapine treated groups.

* 90% power for a 2sided test, at the'5% alpha level, to demonstrateless weight gain w ith quetiapine compared to olanzapine.A total of 95 patients per treatment group (285 patients in total) withvalid AUG (0-2 h) plasma glucose assessments following OGTT atbaseline and at week 24.ittl


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Tabkts to be taken osce dally or BIBJ in accordance with

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Study PlanInsert Study plan from CSP

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seroquel study 125 for marketing purposes

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