Clinical Trial Protocol

Home , Dibenzothiazepine

Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

- Confidential - Confidential - Confidential - Confidential -

Clinical Trial Protocol

Clinical Effectiveness Of The Newer Antipsychotic Compounds Olanzapine, Quetiapine And Aripiprazole In Comparison With Low Dose Conventional Antipsychotics (Haloperidol And Flupentixol) In Patients With Schizophrenia

The Neuroleptic Strategy Study – NeSSy

Protocol-ID.: NeSSy_200901

EudraCT Number 2009-010966-47

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 1 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

Table of contents 1 Abbreviations ...... 4 2 Synopsis...... 5 3 General Information ...... 10 3.1 Protocol Title, Protocol Identifying Number, Date ...... 10 3.2 Sponsor and Monitor ...... 10 3.3 Persons Authorized to Sign the Protocol (Amendments) for the Sponsor ...... 10 3.4 Sponsors’ Medical Experts ...... 10 3.5 Coordinating Investigator ...... 10 3.6 Qualified Physician ...... 11 3.7 Other Medical Departments Involved in the Trial ...... 11 4 Background Information ...... 11 4.1 The Investigational Products ...... 11 4.2 Findings from Clinical Trials...... 11 4.3 Risks of the Investigational Products ...... 13 4.3.1 Olanzapine ...... 13 4.3.2 Quetiapine ...... 13 4.3.3 Aripiprazole ...... 13 4.3.4 Haloperidol ...... 13 4.3.5 Flupentixol ...... 13 4.4 Route of Administration, Dosage (Regimen), Treatment Period ...... 14 4.5 Protocol, Good Clinical Practice (GCP) and Applicable Regulatory Requirements 14 4.6 Description of the Population to be Studied...... 14 5 Trial Objectives and Purpose ...... 15 6 Trial Design ...... 15 6.1 Endpoints ...... 15 6.1.1 Primary Endpoints ...... 15 6.1.2 Secondary Endpoints ...... 15 6.1.3 Adjunctive Secondary Outcome Measures (Efficacy Analyses) ...... 15 6.1.4 Secondary Criteria for Safety Analyses ...... 15 6.2 Type and Design of the Trial ...... 16 6.3 Minimizing / Avoiding of Bias ...... 18 6.3.1 Randomization ...... 18 6.3.2 Blinding ...... 19 6.4 Trial Treatments ...... 19 6.5 Description and Duration of Trial Periods ...... 20 6.6 Study Drug Discontinuation, Early Termination, Drop-outs ...... 20 6.7 Accountability Procedures for Investigational Products ...... 21 6.8 Unmasking of Treatment Assignment...... 21 6.9 Subsequent Treatment after Study Termination ...... 22 6.10 Patients’ Data Collected in the CRF ...... 22 7 Selection and Withdrawal of Subjects ...... 22 7.1 Subject Inclusion Criteria ...... 22 7.2 Subject Exclusion Criteria ...... 23 7.3 Withdrawal Procedures ...... 24 7.3.1 Subject Withdrawal Criteria ...... 24 7.3.2 Data of Withdrawn Subjects ...... 24 7.3.3 Replacement of Withdrawn Subjects ...... 25 7.3.4 Follow-up for Withdrawn Subjects ...... 25 8 Treatment of Subjects ...... 25 8.1 Trial Drugs and Dosage ...... 25 8.2 Concomitant Psychotropic and Non-psychotropic Medication and Treatment .. 25 8.3 Procedures for Monitoring Subject Compliance ...... 26 ------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 2 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

9 Assessment of Efficacy ...... 26 9.1 Specification of the Efficacy Parameters ...... 26 9.1.1 Primary Endpoints ...... 26 9.1.2 Secondary Endpoints ...... 26 9.1.3 Adjunctive Secondary Outcome Measures (Efficacy Analyses) ...... 26 9.2 Assessing, Recording and Analyzing of Efficacy Parameters ...... 27 10 Assessment of Safety ...... 27 10.1 Specification of Safety Parameters...... 27 10.2 Assessing, Recording and Analyzing of Safety Parameters ...... 27 10.3 Adverse Events (AEs) ...... 28 10.4 Follow-up of Subjects after AEs ...... 30 11 Statistics...... 30 11.1 Statistical Methods ...... 30 11.1.1 General items ...... 30 11.1.2 Primary analysis of efficacy ...... 30 11.1.3 Secondary analysis of efficacy ...... 31 11.1.4 Safety analysis ...... 31 11.1.5 Baseline characteristics ...... 32 11.1.6 Additional analyses ...... 32 11.1.7 Interim and subgroup analysis ...... 32 11.2 Sample Size and Power ...... 32 11.2.1 Patients’ Assessment (Quality of Life, SF-36 Measurements)...... 32 11.2.2 Psychiatrists’ Assessment (CGI) ...... 33 11.2.3 Integration of Single Values into AUC ...... 33 11.2.4 Statistical Method to be Used ...... 33 11.2.5 Sample Size Calculation ...... 34 11.2.6 Feasibility of Recruitment ...... 34 11.3 Level of Significance ...... 35 11.4 Criteria for the Termination of the Trial ...... 35 11.5 Procedures for Missing, Unused and Spurious Data ...... 35 11.6 Procedures for Deviations from the Original Statistical Plan ...... 36 11.7 Collectives for Analyses ...... 36 12 Direct Access to Source Data / Documents ...... 36 13 Quality Control and Quality Assurance ...... 37 14 Ethics ...... 38 15 Data Handling and Record Keeping ...... 38 15.1 Safety data ...... 39 16 Financing and Insurance ...... 40 17 Publication Policy ...... 40 18 Supplements ...... 40 18.1 Persons Authorized to Sign the Protocol (Amendments) for the Sponsor ...... 40 18.2 Sponsors’ Medical Experts ...... 40 18.3 Qualified Physician ...... 41 18.4 Other Medical Departments Involved in the Trial ...... 41 18.5 Products used as investigational drugs ...... 41 18.6 DMSB Members ...... 42 19 References to Literature ...... 43

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 3 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

1 Abbreviations AE(s) Adverse Event(s) AIMS Abnormal Involuntary Movement Scale ANCOVA Analysis of Covariance ANOVA Analysis of Variance BARS Barnes Akathisia Rating Scale BMI Body Mass Index CATIE Clinical Antipsychotic Trials of Intervention Effectiveness CGI Clinical Global Impression Score CGI-S Clinical Global Impression Severity Skala CNCM7 Cumulative Needs for Care Monitor (Van-Os-Scale) CRF Case Report / Record File CRP C-reactive protein CUtLASS Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia CW(s) Calendar Week(s) CYP-P450 Cytochrome P450 DISF-SR Derogatis Interview for Sexual Functioning DMSB Data Monitoring and Safety Board EC Ethics Committee ECG Electrocardiogram EPS Extrapyramidal Symptoms Gamma-GT Gamma-Glutamyltransferase GCP Good Clinical Practice GOT Glutamic oxalacetic transaminase (aspartate aminotransferase, AST) GPT Glutamic pyruvic transaminase (alanine aminotransferase, ALT) HbA1c Glycosylated Hemoglobin i.e. In Example ITT Intention-to-Treat KKSB “Kompetenzzentrum für Klinische Studien Bremen“ LDL Low Density Lipoprotein Mini-ICF-P Mini International Classification of Functioning, Disability and Health for Mental Disorders MNS Malignant Neuroleptic Syndrome PANSS Positive and Negative Syndrome Scale PI Principal Investigator PP Per Protocol PSP Personal and Social Performance Scale RWT “Regensburger Wortflüssigkeits-Test“ SAE(s) Serious Adverse Event(s) SAERF Serious Adverse Event Report Form SAS Simpson-Angus-Scale SF-36 Short-Form Health Survey (36 Items) SGAs Second-generation Antipsychotics SWN-K Total Score in Subjective Well-being under Neuroleptic Treatment VLMT “Verbaler Lern- und Merkfähigkeitstest“ Y / N Yes / No (answer options in the Case Report File, CRF)

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 4 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

2 Synopsis

APPLICANT / Prof. Dr. med. Eckart Rüther COORDINATING Universität Bremen, Kooperationszentrum Medizin INVESTIGATOR Universität Göttingen (Prof. em.)

p.A. Kompetenzzentrum für Klinische Studien Am Fallturm 1, TAB 28359 Bremen

Tel.: 089-51605556 FAX: 08157-999115 [email protected]

TITLE OF STUDY Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia Acronym: NeSSy (Neuroleptic Strategy Study) Protocol-ID: NeSSy_200901

CONDITION Schizophrenia (ICD-10 F20.x)

OBJECTIVE(S) This study is designed to compare the efficacy and drug tolerability of two strategies for the treatment of schizophrenia. The two strategies consist of utilizing, on the one hand, a conventional antipsychotic like haloperidol or flupentixol and, on the other hand, a newer antipsychotic compound like olanzapine, quetiapine or aripiprazole in patients with schizophrenia.

INTERVENTION (S) Two strategies: “atypicals” versus “conventional”. Pairs of combinations of the following drugs: 1. Olanzapine orally in daily doses of 10, 15, and 20 mg. 2. Quetiapine (extended release) orally in daily doses of 400, 600, and 800 mg. 3. Aripiprazole orally in daily doses of 10, 15, and 20 mg. 4. Flupentixol orally in daily doses of 6, 9 and 12 mg. 5. Haloperidol orally in daily doses of 3, 4.5, and 6 mg. All treatments are on label in Germany. Study drug administration once daily.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 5 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

KEY INCLUSION AND Key inclusion criteria: EXCLUSION CRITERIA Patients with schizophrenia (ICD-10 F20.x), age 18-65, necessity to establish new or change antipsychotic treatment due to unsatisfying results or side effects. Key exclusion criteria: Acute suicidal tendency, “Einwilligungsvorbehalt (BGB)” or “Unterbringung (PsychKG)“, organic psychosis, history of malignant neuroleptic syndrome, QTc interval ≥ 0.5s / history of congenital QTc prolongation.

OUTCOME(S) Primary efficacy endpoint: Contentment with treatment in 1) patients and 2) psychiatrists; Patient: SF-36 (interviewer version with a time frame of one week); Psychiatrist: CGI. Key secondary endpoints: Subscores of SF-36, SWN-K, PSP, PANSS, matrics (selected centres). Assessment of safety: Adverse events, drop-out rates, SAS / AIMS / BARS and sexual dysfunction changes. Metabolic side effects: body mass index (BMI), waist circumference, HbA1c, fast blood glucose levels, lipid profile. DURATION OF Duration of treatment per patient: 24 calendar weeks (CWs). TREATMENT AND FOLLOW-UP Complete evaluation of all parameters at baseline, 6 weeks, and 24 CWs; primary endpoints and selected parameters additionally at 2, 4 and 12 CWs. Follow-up per patient: 48 CWs.

STUDY TYPE Multi-centre, prospective, randomised for strategies, controlled, double-blind, five substances and two strategies

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 6 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

STATISTICAL Efficacy: ANALYSIS Population for analysis of efficacy alternatively safety is the ITT respectively safety collective consisting of all randomized patients with at least one intake of study drug. Primary criteria of efficacy: SF-36 (patient oriented result) and CGI (psychiatrist assessment) will be analysed by Analysis of covariance (ANCOVA) using AUC values as dependent variables, drug and baseline as independent factors. The null hypothesis of no difference between typical and atypical medication strategy will be tested by linear contrasts and adapted alpha (Bonferroni-Holm procedure). Unequal drug group size will be taken into account. Confidence limits will be calculated. Secondary criteria will be analyzed in an exploratory way. Safety: Safety analysis will be based on diverse aspects of adverse events: EPS, sexual dysfunction, BMI, HbA1c, fast blood glucose levels and lipid profile using pre-post-differences and KW-test.

SAMPLE SIZE To be assessed for eligibility: About 5.400. To be allocated to trial: About 630. To be analysed ITT: About 610 (PP about 300).

TRIAL DURATION Study preparation: 24 CWs. First patient in to last patient out: 168 CWs. Follow-up, data analysis and publication: 24 CWs. Duration of the entire trial: 216 CWs.

PARTICIPATING Approximately 15 in Germany. CENTRES

PREVIOUS DFG / None BMBF PROJECT NUMBER

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 7 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

Schematic diagram of the trial Screening Randomization, Treatment Period Follow baseline -up Visit -1 0 1 2 3 4 5 6 7 Permitted timeframe Day -2 till Day -1 till 0 Day 1 CW 2 CW 4 CW 6 CW 12 CW 24 CW 48 -1 Trial site, examination X X X X X X X X X date Screening, X Informed consent for study1 Random number X X X X X X X X Study drug regimen X X X X X X Study drug compliance2 X X Concomitant lorazepam X X X X X X X X / biperiden medication3 Lorazepam / biperiden X X compliance2 Concomitant X X X X X X psychiatric medication / treatment4 Concomitant X X X X nonpsychiatric medication / treatment4 Blood pressure, heart X X X frequency ECG X X SF-36, CGI X X X X X X X SWN-K, PSP, PANSS X X X Adjunctive secondary X X X outcome measures5 “Mehrfachwahl- X wortschatztest (B)“ Height X Weight, waist X X X X X X X X circumference Blood safety analyses6 X X X Serum level analyses7 X X EPS8, sexual X X X X X X X dysfunctions AEs X X X X X X X X Study continuation X X X X X X X

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 8 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

 General items: o Trial site and examination date at days -2 till -1, -1 till 0, 1 and in calendar weeks (CWs) 2, 4, 6, 12, 24 and 48 (visits -1 to 7). o Random number at days -1 till 0, 1 and in CWs 2, 4, 6, 12, 24 and 48 (visits 0-7).  Screening, Informed consent for study: o Screening number, inclusion / exclusion criteria, informed consent for study, relevant medical and past psychiatric history, date of birth, gender, ethnicity and βHCG in urine at days -2 till -1 (visit -1).  Randomization at days -1 till 0 (visit 0).  Medication / treatment: o Regimen of study drug at day 1 and in CWs 2, 4, 6, 12 and 24 (visits 1-6). o Study drug compliance check in CWs 6 and 24 (visits 4 and 6): remaining capsules. o Concomitant lorazepam / biperiden medication check at days -1 till 0, 1 and in CWs 2, 4, 6, 12, 24 and 48 (visits 0-7): daily dose, start and stop date (or ‘ongoing’). o Lorazepam and biperiden compliance check in CWs 6 and 24 (visits 4 and 6): remaining tablets. o Concomitant psychiatric medication / treatment check at days -1 till 0, 1 and in CWs 2, 6, 24 and 48 (visits 0-2, 4, 6-7): dose, application, start and stop date (or ‘ongoing’), reason for use. o Concomitant nonpsychiatric medication / treatment check at days -1 till 0 and in CWs 6, 24 and 48 (visits 0, 4 and 6-7): dose, application, start and stop date (or ‘ongoing’), reason for use.  Vital signs: o Blood pressure (sitting position) and heart frequency at days -1 till 0, CWs 4 and 24 (visits 0, 3 and 6). o ECG at days -1 till 0 and in CW 4 (visits 0 and 3).  Primary and secondary endpoints: o SF-36 and CGI-S at days -1 till 0 (visit 0) and SF-36 and CGI-improvement in CWs 2, 4, 6, 12, 24 and 48 (visits 2-7). o SWN-K, PSP and PANSS at days -1 till 0 and in CWs 6 and 24 (visits 0, 4 and 6).  Adjunctive secondary outcome measures: o CGI-S, CGI-matrix, Mini-ICF-P, Trail Making Test (A, B), “RWT”, “Buchstaben-Zahlen- Test”, “VLMT (A, C, D)”, CNCM7, DISF-SR at days -1 till 0 and in CWs 6 and 24 (visits 0, 4 and 6). o “Mehrfachwahlwortschatztest (B)” at days -1 till 0  Safety outcome measures: o Height at days -1 till 0 (visit 0). o Weight and waist circumference at days -1 till 0, 1 and in CWs 2, 4, 6, 12, 24 and 48 (visits 0-7). o Blood safety analyses (Hematology, HbA1c, fast blood glucose level, GOT, GPT, Gamma-GT, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, creatinine, CRP) at days -1 till 0 and in CWs 6 and 24 (visits 0, 4 and 6). o Serum level analyses (serum levels of the respective study drug (olanzapine, quetiapine, aripiprazole, haloperidol, flupentixol)) in CWs 6 and 24 (visits 4 and 6). o SAS, AIMS, BARS and sexual dysfunctions at days -1 till 0, 1 and in CWs 2, 4, 6, 12, 24 and 48 (visits 0-7). o AEs at days -1 till 0, 1 and in CWs 2, 4, 6, 12, 24 and 48 (visits 0 to 7): treatment necessary Y / N specification, date, related to study drug, severity, outcome.  Study continuation at days -1 till 0, 1 and in CWs 2, 4, 6, 12 and 24 (visits 0 to 6): per-protocol Y / N specification, reason, last observation.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 9 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

3 General Information

3.1 Protocol Title, Protocol Identifying Number, Date The protocol title is: Clinical Effectiveness Of The Newer Antipsychotic Compounds Olanzapine, Quetiapine And Aripiprazole In Comparison With Low Dose Conventional Antipsychotics (Haloperidol And Flupentixol) In Patients With Schizophrenia - The Neuroleptic Strategy Study (NeSSy). The protocol identifying number is: NeSSy_200901, the EudraCT Number is 2009-010966-47. Date: February 18th, 2009.

3.2 Sponsor and Monitor There is no pharmaceutical or other commercial sponsor of this multicenter trial. Therefore, the institution which performs the trial has to attend to the Sponsors responsibilities. The Universität Bremen (Bibliothekstraße 1, 28359 Bremen) is the sponsor. The monitor of the study is Prof. Dr. med. Bernd Mühlbauer, Institut für Pharmakologie, Klinikum Bremen-Mitte, St.-Jürgen-Str.1, 28177 Bremen. The study will be funded by research funds of the Federal Ministry of Education and Research (BMBF).

3.3 Persons Authorized to Sign the Protocol (Amendments) for the Sponsor For all information see the document attached in the supplements (see 18.1 Persons Authorized to Sign the Protocol (Amendments) for the Sponsor).

Amendments to the protocol No changes or additions to the protocol may be made unless it is approved by the EC and by the Legal Authority. Exceptions from this regulation can only be made in case patient’s safety appears to be threatened. If there is an approval, the changes have to be documented by a Written Protocol Amendment. The amendment has to be sent to all investigators. Irrespective of the need for approval of a formal protocol amendment each investigator is committed to take immediately any action that she / he considers necessary in the interest of any patient's safety, even if such action would be a protocol deviation. In such cases, the PI has to be informed instantly about this action. The PI of the site will inform the coordinating investigator and the sponsor who will inform the EC and the Legal Authority within ten working days.

3.4 Sponsors’ Medical Experts For all information see the document attached in the supplements (see 18.2 Sponsors’ Medical Experts).

3.5 Coordinating Investigator The coordinating investigator is Professor Dr. med. Eckart Rüther.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 10 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

3.6 Qualified Physician For all information see the document attached in the supplements (see 18.3 Qualified Physician).

3.7 Other Medical Departments Involved in the Trial For all information see the document attached in the supplements (see 18.4 Other Medical Departments Involved in the Trial).

4 Background Information

4.1 The Investigational Products  Olanzapine: Olanzapine is an antipsychotic agent (thienobenzodiazepine derivative) structurally similar to clozapine and both a dopamine (D) and serotonin (5-HT) antagonist. Pharmacologic effects of olanzapine are also similar to those of clozapine, and both agents are classified as "atypical" antipsychotic agents mainly by virtue of their efficacy in treating negative (and positive) symptoms of schizophrenia and lower propensity for extrapyramidal effects compared to conventional or typical antipsychotics (eg, haloperidol) (Anon, 1994).  Quetiapine: Quetiapine is a dibenzothiazepine antipsychotic agent bearing structural similarity to clozapine and olanzapine (Green, 1999). Quetiapine has been shown to have affinity for multiple neurotransmitter receptors in in vitro binding studies. The drug exhibits high affinity for serotonergic type 2 (5-HT2) receptors and moderate affinity for dopamine type 2 (D2) receptors, whereas antagonism of D1 and 5-HT1A receptors is relatively weak. Appreciable affinity for alpha-1 adrenergic, alpha-2 adrenergic, and histamine H1 receptors has also been observed (Fulton et al., 1995). Quetiapine may be less likely than clozapine to induce anticholinergic and antiadrenergic effects.  Aripiprazole: Aripiprazole is an atypical antipsychotic agent (quinolinone derivative). It exhibits relatively high affinity for dopamine D2 and D3 receptors and serotonin 5-HT1A and 5-HT2A receptors. The efficacy of the drug in schizophrenia appears related to partial agonist activity at D2 and 5-HT1A receptors (Lawler et al., 1999).  Haloperidol: Similar to other neuroleptics, haloperidol centrally blocks the action of dopamine by binding previously to DA-2 receptors, and to a lesser extent, DA-1 receptors (Snyder, 1981). Haloperidol is pharmacologically related to the piperazine phenothiazines (Ayd, 1978).  Flupentixol: Flupenthixol is a piperidine-substituted thioxanthene neuroleptic which is structurally similar to thiothixene. It exists as the cis(Z) and trans(E) isomers; only the cis(Z) isomer is active (Balant-Gorgia et al, 1985). Like other neuroleptics, flupenthixol is an antagonist at postsynaptic D1 and D2 dopamine receptor.

4.2 Findings from Clinical Trials The discovery of the antipsychotic actions of chlorpromazine and reserpine in the fifth decade of the 20th century has revolutionized psychiatry. It was the basis for the discharge of countless patients with chronic psychoses from psychiatric state hospitals (“deinstitutionalization”). This process led to a huge reduction in psychiatric inpatient beds in all industrialized countries worldwide. Although butyrophenones with its prototype haloperidol were introduced already in 1958, tricyclic antipsychotics remained the mainstay for the treatment of schizophrenia and mania for many years, and their structure formed the basis for several of the second-generation antipsychotics such as clozapine, olanzapine, and quetiapine. These and other compounds such as risperidone, ziprasidone, and aripiprazole were later grouped together as “atypical” antipsychotics. Originating from the observation

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 11 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

that clozapine was superior to other antipsychotics not only with regard to extrapyramidal side effects but also in several other clinical respects (Kane et al., 1988), it was hoped that the ideal “atypical” antipsychotic molecule should be effective against positive, negative, and cognitive symptoms, while at the same time lacking extrapyramidal symptoms (EPS) and prolactin elevation. This led to a broadening of the concept “atypicality” (Kinon and Lieberman, 1996). Almost two decades of search for the “miracle molecule” with efficacy against all heterogeneous phenomena associated with the complex group of diseases called “schizophrenia” produced a lot of disappointment. Although the superior tolerability of the second-generation antipsychotics (SGAs) with regard to the incidence of EPS has been shown in numerous clinical trials and meta-analyses (Correll et al., 2004), the dose of the standard comparator haloperidol had been usually chosen unfairly high. Studies with very low haloperidol doses that still show increased incidences of tardive dyskinesia have been criticized for their methodological flaws (Jeste et al., 1999). Furthermore, new detrimental side-effects such as weight gain attracted attention with use of some of the SGAs (Newcomer, 2007).

The superior efficacy of the SGAs with regard to improvement of positive and negative symptoms was demonstrated in meta-analyses (Davis et al., 2003), but it has been increasingly questioned recently that studies on the efficacy and safety of antipsychotics, which are usually sponsored by the pharmaceutical industry with the purpose of getting approval for their investigational drugs, provide useful information on treatment efficacy under clinical conditions (“real world”). Therefore, “efficacy” studies have been complemented by “effectiveness” studies. The studies which gained the most attention are the „Clinical Antipsychotic Trials of Intervention Effectiveness“ (CATIE) (Lieberman et al., 2005a) and the „Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia“ (CUtLASS) trial (Jones et al., 2006). These studies focussed on questions of treatment adherence and quality of life. Despite their profound methodological weaknesses, these studies questioned the superiority of second-generation over first-generation antipsychotics. Finally, it has not been shown unequivocally that any of the available SGAs is superior to the compounds from the first-generation antipsychotics (FGAs) with regard to improvement of the cognitive deficits associated with schizophrenia, and the effects of all compounds in this domain are small. In the CATIE study, after 18 months treatment the classical comparator perphenazine was even significantly superior to olanzapine and risperidone with regard to cognitive effects (Keefe et al., 2007). However, only about 300 of the initially included 1500 patients were evaluated at this late time point.

Both the CATIE and the CUtLASS study suffer from profound methodological flaws. Some of the second-generation antipsychotics were not adequately dosed in the CATIE study, and patients with tardive dyskinesia were excluded from treatment with perphenazine, introducing a selection bias (Lieberman et al., 2005a). In the CUtLASS study, about one half of the patients in the first-generation treatment arm were treated with sulpiride (Jones et al., 2006), a compound which many clinicians and researchers would consider a second-generation antipsychotic.

Since the publication of the first placebo-controlled trial on the efficacy of chlorpromazine in patients with schizophrenia by Elkes and Elkes in 1954 (Elkes and Elkes, 1954), the methodology of clinical trials in schizophrenia has been constantly refined, and the randomized, placebo-controlled trial in parallel groups is considered the gold-standard (for review see Stroup et al., 2006). However, these studies have profound weaknesses. Most studies are short-term studies which do not allow inclusion of patients with comorbid disorders. Use of concomitant medication is usually also restricted. Therefore, the generalizability of these studies is limited, because comorbid disorders are very common in clinical practice, and many patients are treated with a variety of different - psychotropic and

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 12 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

non-psychotropic - medications. For example, although comorbid substance abuse is extremely common in patients with schizophrenia, this patient group is usually excluded from participation in efficacy trials. It is therefore unknown whether the results from those studies are transferable to patients with comorbid substance abuse. Similar is true for patients with severe medical and neurological disorders.

Furthermore, the selection of the Primary Endpoints in clinical trials with antipsychotics has been recently questioned. The efficacy of an antipsychotic is usually quantified with the reduction of positive symptoms. This is usually tested in patients with an acute psychotic exacerbation or in patients who not adequately respond to a previous treatment. The efficacies against negative or cognitive symptoms are usually considered just secondary endpoints or they are investigated in sub-populations of the total sample in multi-centre trials. The efficacy against residual symptoms or factors such as long-term efficacy, quality of life or care-taker burden has also been rarely studied.

Primary Endpoints in clinical studies in first-episode patients with schizophrenia are usually the time to remission of (positive) symptoms and the proportion of patients which obtains remission. The threshold for remission is usually higher in studies with first-episode patients (e.g., reduction of Positive and Negative Syndrome Scale (PANSS) total score > 50%) than in studies with chronic patients (> 30%, sometimes just > 20%). Only recently other dimensions such as efficacy against cognitive symptoms or time until relapse have been regarded as Primary Endpoints. The value of studies in which biological parameters (e.g., brain volumes) were considered surrogate markers for disease progression is currently unclear (Lieberman et al., 2005b). Primary endpoints in long-term (observation period ≥ six months) studies are usually relapse and rehospitalization rates, while they focus on reduction of positive and negative symptoms. Affective and especially cognitive symptoms have recently gained increased attention. Few studies focus on treatment-resistant patients.

4.3 Risks of the Investigational Products

4.3.1 Olanzapine For all information see the current product information.

4.3.2 Quetiapine For all information see the current product information.

4.3.3 Aripiprazole For all information see the current product information.

4.3.4 Haloperidol For all information see the current summary of product characteristics.

4.3.5 Flupentixol For all information see the current summary of product characteristics.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 13 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

4.4 Route of Administration, Dosage (Regimen), Treatment Period All trial drugs will be taken – in a double-dummy intake (see 6.4 Trial Treatments) - as whole, unchewed and undivided capsule in the morning (between 8 and 9 am) and in the evening (between 8 and 9 pm). The oral application form is the less invasive measure ensuring the best patient’s autonomy with related efficacy as with an intramuscular application form (Gaebel et al., 2006). The daily oral dosage will be 2-4 capsules of a basic dose of each drug, contained in one capsule: olanzapine 5 mg; quetiapine (extended release) 200 mg; aripiprazole 5 mg; flupentixol 3 mg; haloperidol 1.5 mg. In the initial two study weeks a starting dosage of one capsule per day can be used. After that the standard dosages of the trial have to be achieved (olanzapine 10-20 mg, quetiapine 400-800 mg, aripiprazole 10-20 mg, haloperidol 3-6 mg, flupentixol 6-12 mg). These dosages respectively dosage regimes refer to those advised in the German literature (Gaebel et al., 2006). The dosage of aripiprazol was decided upon following the clinical experience of the researchers involved and to avoid problems with the start-up dosage; this will be accounted for in the discussion of the study results. The treatment period of 24 CWs and the follow-up after further 24 CWs will provide sufficient data about short-term and long-term efficacy as well as adequate information about possible side effects. First patient in to last patient out will be after 24 months, first patient in to last patient follow-up after 36 months. After closing-out the last patient recruited, data will be frozen and submitted to the study personnel responsible for biometrical calculation and statistics. Lorazepam, up to daily oral 7.5 mg, as concomitant antipsychotic treatment and biperiden, up to daily oral 8 mg, for the handling of possible neurologic side effects can be used at any time during the treatment period, according to the current summary of product characteristics.

4.5 Protocol, Good Clinical Practice (GCP) and Applicable Regulatory Requirements The study will be conducted according to the standards of Good Clinical Practice (GCP) and German drug law. The study must not be initiated before permission of the Federal Institute for Drugs and Medical Devices (BfArM) and the responsible ethical committee have been received. The ethical tenability for conducting this study is given since all patients will receive an active therapy. An independent Data Monitoring and Safety Board (DMSB) will supervise the study to warrant individual and general patient safety. Insurance will be set up.

4.6 Description of the Population to be Studied The trial aims to include a broad spectrum of patients with schizophrenia (ICD-10 F20.x): patients of either gender aged between 18 and 65 years and need for a new or change of an antipsychotic treatment due to unsatisfying results or side effects. Such patients presenting at one of the clinical psychiatric departments included as study sites will be screened for inclusion and exclusion criteria described in 7.1 and 7.2 and asked for informed consent to participation.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 14 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

5 Trial Objectives and Purpose

This study is designed to compare the efficacy and drug tolerability of two strategies for the treatment of schizophrenia. The two strategies consist of utilizing, on the one hand, a conventional antipsychotic like haloperidol or flupentixol and, on the other hand, a newer antipsychotic compound like olanzapine, quetiapine or aripiprazole in patients with schizophrenia. The study aims to represent the situation in the daily clinical setting. Study results will be published to provide data and help physicians improve the clinical management of patients with schizophrenia.

6 Trial Design

6.1 Endpoints

6.1.1 Primary Endpoints  Change from baseline to CW 24 (visit 6) in the total score of SF-36 (interviewer version with a time frame of one week) and CGI (both measured with AUC, see 9.1.1 for details)

6.1.2 Secondary Endpoints  Subscores of SF-36 (AUC, logtime)  SWN-K  PSP (family member rating, rating by oneself, family member questionnaire)  PANSS

6.1.3 Adjunctive Secondary Outcome Measures (Efficacy Analyses)  CGI-S  CGI-matrix  Mini-ICF-Rating for Mental Disorders (Mini-ICF-P)  Trail Making Test (A and B)  “Regensburger Wortflüssigkeits-Test (RWT)“  “Buchstaben-Zahlen-Test”  “Verbaler Lern- und Merkfähigkeitstest (VLMT, A, C, D)“  “Mehrfachwahlwortschatztest (B)”  CNCM7 (Cumulative Needs for Care Monitor, Van-Os-Scale)  DISF-SR

6.1.4 Secondary Criteria for Safety Analyses  Adverse events  Drop-out rates between the groups  SAS / AIMS / BARS and sexual dysfunction changes from baseline to CW 24 (visit 6)  Metabolic side effects: BMI, waist circumference, HbA1c, fast blood glucose levels and lipid profile changes (total cholesterol / LDL-cholesterol / HDL-cholesterol / triglycerides) from baseline to CW 24 (visit 6)  Serum levels of the respective study drug (olanzapine, quetiapine, aripiprazole, haloperidol, flupentixol)

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 15 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

6.2 Type and Design of the Trial The trial will be a prospective, randomized, controlled, double-blind and multi-center study type with five study drugs and two treatment strategies.

1 Screening number, inclusion / exclusion criteria, relevant medical and psychiatric history, date of birth, gender, ethnicity, pregnancy test (βHCG in urine) 2 Check of remaining capsules 3 Check of daily dose, start and stop date (or ‘ongoing’) 4 Check of dose, application, start and stop date (or ‘ongoing’), reason for use 5 CGI-S, CGI-matrix, Mini-ICF-P, Trail Making Test (A, B), “RWT”, “Buchstaben-Zahlen-Test”, “VLMT (A, C, D)”, Cumulative Needs for Care Monitor (Van-Os-Scale, CNCM7), DISF-SR 6 Hematology, HbA1c, fast blood glucose level, GOT, GPT, Gamma-GT, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, creatinine, CRP 7 Serum levels of the respective study drug (olanzapine, quetiapine, aripiprazole, haloperidol, flupentixol) 8 SAS, Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS) ------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 16 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 17 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

6.3 Minimizing / Avoiding of Bias

6.3.1 Randomization Randomization and double-blind design will support the generation of unbiased data. Selection bias will significantly be reduced by the design described below and controlled by screening logs. This trial compares two strategies: treatment with conventional (“typical”) drugs versus “atypical” drugs. Allocation of patients to one of these strategies is randomized. The randomization procedure reflects the diversity of diagnostics and patient status by offering a limited choice of drugs to be applied to each patient. A total of five drugs will be used; two of them (haloperidol and flupentixol) are classified as “typical” and the remaining as “atypical”. From the 5 basic drugs, 6 pairs consisting of one “typical” and one “atypical” can be formed: Pair 1: haloperidol versus olanzapine Pair 2: haloperidol versus aripiprazole Pair 3: haloperidol versus quetiapine Pair 4: flupentixol versus olanzapine Pair 5: flupentixol versus aripiprazole Pair 6: flupentixol versus quetiapine The randomization process for one patient consists of two steps. In step 1, a random choice of two pairs from the list above is allocated to the patient. The investigator is informed about these possibilities and decides which pair is more suitable for this specific case. In step 2, a further random decision selects either the “typical” or the “atypical” drug from the pair determined in step 1 as the drug to be actually applied. The technical realization of this process is as follows. In step 1, a combination of two pairs is randomly selected from the set of all 15 possible 2-pair combinations. Using the pair numbers from above, these combinations are: (1,2) (1,3) (1,4) (1,5) (1,6) (2,3) (2,4) (2,5) (2,6) (3,4) (3,5) (3,6) (4,5) (4,6) (5,6) The 2-pair combination for a patient is selected randomly, but not blinded. After the investigator has chosen one of the pairs from the 2-pair combination, the drug (“typical” or “atypical”) to be used from the chosen pair is found in step 2 by blinded randomization. Thus, 30 combinations of “typical”-“atypical” pairs (15 possibilities) with the subsequent choice between “typical” and “atypical” (two possibilities) are randomized to patient numbers. For each random number and both associated comparative pairs of drugs the actual randomized choice of its “typical” or “atypical” component (step 2) will be computed and documented in a sealed random list. Drugs will be packaged and delivered in two containers for each random number: one containing the randomized “typical” or “atypical” component of comparative pair 1 and the other that of comparative pair 2. The patient will receive the drugs from the container corresponding to the investigator’s choice of comparative pair 1 or 2.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 18 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

6.3.2 Blinding The following blinding design will support the generation of unbiased data. The 2-pair combination allocated to a patient by step 1 of the random process will not be visible for the investigator until the patient is enrolled. Tablets of all 5 drugs to be investigated will be hidden in neutral capsules. As one drug (aripiprazole) is to be applied in the morning and the remaining in the evening, there will be an additional application of placebo tablets in neutral capsules such that each patient receives a morning and an evening capsule. The following scheme will be used: Investigational drug Morning capsule Evening capsule according to randomization: containing containing Aripiprazole verum placebo other placebo verum The central packing process will use the randomlist sealed after use. Packages of investigational drugs will present random number and coding for the respective comparative pair of drugs but no information about the random choice of “typical” or “atypical” drug contained in its capsules. Thus the final choice of the “typical” or the “atypical” drug in step 2 remains in double blind condition for the whole trial as long as no code breaking is initialized by the safety monitoring process. Masking of patients, investigators, members of the study site personnel, and members of the Blinded Evaluation Center (BEC) to the identity of treatment will insure concealed and unbiased investigation, treatment and evaluation. Measurements of the study drug serum concentrations are performed in CW four and six (visit 4 and 6). Additional measurements can be conducted if required for safety reasons. In order to avoid unblinding the results of these measurements will be forwarded to the investigators without naming the compound nor the exact concentration value. Instead, the concentration will be communicated as one of the following: - "below therapeutic concentration range" - "within therapeutic concentration range" - "above therapeutic concentration range" For this purpose, the concentrations measured are compared with the range information described in the Consensus Guidelines of the “TDM-Konsensgruppe der Arbeitsgemein- schaft für neuropsycho-pharmakologie und Pharmakopsychiatrie” (AGNP) as communicated by Prof. Dr. Hiemke (Mainz).

6.4 Trial Treatments The Treatment Period will begin when the patient is randomized to the study drug and end at CW 24 or until failure of therapeutic response or until occurrence of major / intolerable adverse events. After randomization the appropriate treatment is administered once daily in each patient. The daily oral dosage will be 2-4 capsules of a basic dose of each drug: olanzapine 5mg; quetiapine 200mg; aripiprazole 5mg; flupentixol 3mg and haloperidol 1,5mg. The dosage between two and four capsules can be chosen according to clinical needs. In the initial two study CWs a starting dosage of one capsule per day can be used. After that the standard dosages of the trial have to be achieved (olanzapine 10-20 mg, quetiapine 400-800 mg, aripiprazole 10-20 mg, haloperidol 3-6 mg, flupentixol 6-12 mg). Aripiprazole will be the only study drug to be ingested in the morning, all other study drugs will be taken in the evening. To prevent an unmasking of the administered study drugs, there

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 19 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

will be a double-dummy intake of the study drugs: All patients will receive encapsulated tablets for the morning and for the evening taking; the capsules for the morning intake will contain aripiprazole or placebo, the capsules for the evening intake olanzapine, quetiapine, haloperidol, flupentixol or placebo. At visit 1-6 the patients will obtain the required volume of study drugs and lorazepam as well as biperiden for getting along with up to the next visit. During the first two CWs of the study a pre-medication with other psychotropic drugs, including antipsychotics can be continued. (See 8.2 for details of concomitant medication.)

6.5 Description and Duration of Trial Periods The recruitment of appropriate subjects for the study will be initiated immediately after approval by the Legal Authority and the Ethics Committee (EC) which is expected in October 2009. For the individual patient, the study consists of four periods: a screening period, the randomization, a treatment period and the follow-up. When the patient signs the Informed Consent Form for the study the screening period will begin. It requires up to two days and will end with the patient’s inclusion in the study and randomization to a treatment arm only in case of eligibility of the patient. If the patient is not eligible, there will be no inclusion in the study. During the screening period the eligibility of the consenting patients will be verified. The examination for evaluating the eligibility of the patients for the study includes reviewing the inclusion and exclusion criteria as well as the results of the blood analyses and ECG. The investigator will assess the results of the examinations and approve eligibility. After the randomization (baseline: day -1 till day 0) the treatment period will start with 6 further visits: at day one (visit 1) and in CW two, four, six, twelve and 24 (visits 2-6). A follow-up with physical examination will be conducted at CW 48 (visit 7) or 24 CWs after an early termination of the study. First patient in to last patient out will be after 42 months, first patient in to last patient follow- up after 48 months. After closing-out the last patient recruited, data will be frozen and submitted to the study personnel responsible for biometrical calculation and statistics. The end of the trial is defined by data base lock.

6.6 Study Drug Discontinuation, Early Termination, Drop-outs The investigator will terminate the study attendance of an individual patient in case of a failure of therapeutic response or an occurrence of major / intolerable adverse events. If the investigator defines that further application of the study drug would result in a safety risk for the patient the intake of the study drug within the study must be terminated. Occurrence of any of the following adverse events (AEs) requires a discontinuation of the study drug:  Acute suicidal tendency  Newly-arranged “Einwilligungsvorbehalt (BGB)” or “Unterbringung (PsychKG)“  MNS or unclearly high fever

 QTc interval prolongation > 0,01s  New onset of ECG-signs of ventricular tachycardia or ventricular flutter or ventricular fibrillation  GOT / GPT / Gamma-GT > fivefold increase of the upper normal value with initial normal values ------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 20 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

 Hepatitis including hepatocellular or cholestatic liver damage or a hybrid form  Neutropenia (neutrophiles < 1,0 x 109 / l)  Fast blood glucose levels ≥ 300 mg / dl  Glycosylated hemoglobin (HbA1c) ≥ 10 %  Hypertriglyceridemia ≥ 500 mg / dl requiring treatment and the absence of hyperglucosemia  Newly-discovered untreated hyperthyreosis  Newly-discovered pregnancy  Interruption of study medication > 2 CWs If the investigator is convinced that, for any other reason, continuation of study drug application would be unfavourable for the patient’s health, the study drug has to be discontinued. This decision must be well-founded on best clinical judgment and must estimate the benefit of therapeutic effect and the risk of the treatment for each patient. Study participation will be stopped with an interruption of study medication for more than two weeks. All patients with an early termination will be followed up for further 24 CWs for explorative analyses of the Primary Endpoints. In case of an early termination it will be attempted to perform visit 6 (on schedule in CW 24) immediately. In case of early terminations the last observation carried forward (LOCF) principle will be used for all endpoint analyses. After study drug discontinuation a patient should continue the study follow-up after 24 CWs. A Study Conclusion Form has to be completed in the appropriate CRF pages, recording the date and primary reason for discontinuing the study drug. The sponsor reserves the right to discontinue the study at any time after discussion with the coordinating investigator, if he comes to the conclusion that, in the case of continuation, the risk of harm for the patients might prevail over their potential individual benefit or over the scientific interest within this group of patients.

6.7 Accountability Procedures for Investigational Products In CW six (visit 4) and in CW 24 (visit 6), at the end of the treatment period, there will be a pill count of the remaining capsules for each patient. Moreover each study site will control the returned study drugs at the end of the study.

6.8 Unmasking of Treatment Assignment The patient’s allocation to a treatment arm will immediately be unmasked after the regular Treatment Period. Having completed all necessary investigations at CW 24 (visit 6) the investigator performs the code break to decide on the subsequent psychiatric treatment. In case of an emergency the possibility to unmask the patient’s allocation to a treatment arm during the active treatment study period has to be guaranteed. An Emergency Sheet with code information will be available at all investigators’ sites. It provides information of the treatment drug for each patient and is kept, in sealed and darkened envelopes, in safe but accessible places. The patient’s envelope may only be opened in case of emergency.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 21 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

The investigator will record date, time and reason for unmasking and must keep this information with the CRF, without presenting the unmasked treatment code on the CRF. The coordinating investigator has to be informed immediately after breaking the code. If, at the investigator's site, no member of the study team can be reached for such emergency code break the sponsor's staff has to warrant the availability of such emergency unmasking information by storing a second set of emergency sheets.

6.9 Subsequent Treatment after Study Termination After a regular completion or an early termination of the study the patients will be subsequently treated according to the decision of the attending doctor. Various efficacious and approved drugs are available for the therapy of schizophrenia.

6.10 Patients’ Data Collected in the CRF Patient characteristics as described in section 6.2 will be collected for each patient, recorded in the CRF. All study drugs (including lorazepam as an additional psychotropic medication and biperiden for the handling of possible neurologic side effects allowed during the study period) administered to the patient during the study must be reported on the appropriate Visit Form (visit 1 to 6) of the Case Report File (CRF). Deviations from the protocol for the administration of olanzapine, quetiapine, aripiprazole, haloperidol or flupentixol must be described on the appropriate Visit Form of the CRF. Information about patients who withdraw from the study, including patient’s number, initials, last administration of study drug as well as lorazepam and biperiden, date of early termination and the primary reason for not continuing will be obtained and recorded on the Study Conclusion Form. All information noted in the CRFs must by traceable to the respective source data. Other data which can be recorded directly on the CRFs will be defined before study start, and they will be accepted as the source data.

7 Selection and Withdrawal of Subjects

7.1 Subject Inclusion Criteria Patients of either gender, aged 18-65 years  Schizophrenia (ICD-10 F20.x)  Necessity to establish a new or change of an antipsychotic treatment due to unsatisfying results or side effects  Written informed consent (of patient and “Betreuer” in case of patients with “rechtliche Betreuung”) All patients in compliance with inclusion criteria are offered enrolment in the study.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 22 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

7.2 Subject Exclusion Criteria  Known or suspected hypersensitivity to olanzapine, quetiapine, aripiprazole, flupentixol or haloperidol  Acute suicidal tendency  “Einwilligungsvorbehalt (BGB)” or “Unterbringung (PsychKG)“  Epilepsy  Organic psychosis  Parkinson Disease  Dementia  History of MNS  Recent myocardial infarction (< 3 months)  QTc interval ≥ 0.5s, history of congenital QTc prolongation  Actual ECG-signs of ventricular tachycardia, history of or actual ECG-signs of ventricular flutter or ventricular fibrillation  Uncompensated congestive heart failure  Complete Left bundle branch block (LBBB)  History of or actual signs of thromboembolism  Hepatitis including hepatocellular or cholestatic liver dammage  Neutropenia (neutrophiles < 1,0 x 109 / l)  Myeloproliferative disorders  Mamma tumor  Untreated hyperthyreosis  Glaucoma  Women with child bearing-potential without safe contraception  Pregnancy and / or breast-feeding  Hereditary galactose or fructose intolerance, deficiency of lactase or saccharase- isomaltase, glucose-galactose-malabsorption  History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk for treatment complications  Concomitant treatment with cytochrome-P-450-3A4-inhibitors (as HIV-protease- antagonists, antimycotics of the azole type, erythromycin and clarithromycin), drugs containing reserpine or drugs possibly increasing the QTc-interval (e.g. anti- arrhythmics of the class IA or III, antibiotics of the macrolide type or antihistaminics)  Participation or previous participation in any studies of investigational drugs within one month preceding day 0 (excluding vitamins and minerals)  Inability to comply with study or follow-up procedures

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 23 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

7.3 Withdrawal Procedures

7.3.1 Subject Withdrawal Criteria The investigator will terminate the study attendance of an individual patient in case of a failure of therapeutic response or an occurrence of major / intolerable adverse events. If the investigator defines that further application of the study drug would result in a safety risk for the patient the intake of the study drug within the study must be terminated. Occurrence of any of the following adverse events (AEs) requires a discontinuation of the study drug:  Acute suicidal tendency  Newly-arranged “Einwilligungsvorbehalt (BGB)” or “Unterbringung (PsychKG)“  MNS or unclearly high fever  QTc interval prolongation > 0,01s  New onset of ECG-signs of ventricular tachycardia or ventricular flutter or ventricular fibrillation  GOT / GPT / Gamma-GT > fivefold increase of the upper normal value with initial normal values  Hepatitis including hepatocellular or cholestatic liver dammage  Neutropenia (neutrophiles < 1,0 x 109 / l)  Fast blood glucose levels ≥ 300 mg / dl  Glycosylated hemoglobin (HbA1c) ≥ 10 %  Hypertriglyceridemia ≥ 500 mg / dl requiring treatment and the absence of hyperglucosemia  Newly-discovered untreated hyperthyreosis  Newly-discovered pregnancy  Interruption of study medication > 2 CWs If the investigator is convinced that, for any other reason, continuation of study drug application would be unfavourable for the patient’s health, the study drug has to be discontinued. This decision must be well-founded on best clinical judgment and must estimate the benefit of therapeutic effect or the risk of the treatment for each patient. Study participation will be stopped with an interruption of study medication for more than two weeks. The discontinuation of the study drug will be performed in a slow dose reduction over a longer period to prevent any abstinence phenomena. The sponsor reserves the right to discontinue the study at any time after discussion with the coordinating investigator, if he comes to the conclusion that, in the case of continuation, the risk of harm for the patients might prevail over their potential individual benefit or over the scientific interest within this group of patients.

7.3.2 Data of Withdrawn Subjects In case of an early termination, it will be attempted to perform visit 6 (on schedule in CW 24) immediately. In case of early terminations the last observation carried forward (LOCF) principle will be used for all endpoint analyses. A Study Conclusion Form has to be completed in the appropriate CRF pages, recording the date and primary reason for discontinuing the study drug.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 24 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

7.3.3 Replacement of Withdrawn Subjects As the investigators decided to use a cautious estimate of 50 % dropout rate for the sample size proposal, there will be no replacement of withdrawn subjects.

7.3.4 Follow-up for Withdrawn Subjects All patients with an early termination will be followed up for further 24 CWs for explorative analyses of the Primary Endpoints.

8 Treatment of Subjects

8.1 Trial Drugs and Dosage The daily oral dosage will be 2-4 capsules of a basic dose of each drug, contained in one capsule: olanzapine 5 mg; quetiapine (extended release) 200 mg; aripiprazole 5 mg; flupentixol 3 mg; haloperidol 1.5 mg. In the initial two study weeks a starting dosage of one capsule per day can be used. After that the standard dosages of the trial have to be achieved (olanzapine 10-20 mg, quetiapine 400-800 mg, aripiprazole 10-20 mg, haloperidol 3-6 mg, flupentixol 6-12 mg). Study-associated treatment and examination is scheduled for 24 CWs. 24 CWs after the last study visit, each patient will be examined by study personnel as far as possible to follow-up the treatment response as well as to observe for potential untoward long-term effects. First patient in to last patient out will be after 24 months, first patient in to last patient follow-up after 36 months. After closing-out the last patient recruited, data will be frozen and submitted to the study personnel responsible for biometrical calculation and statistics.

8.2 Concomitant Psychotropic and Non-psychotropic Medication and Treatment As an additional treatment lorazepam up to daily oral 7.5 mg and biperiden up to daily oral 8 mg can be used if there is no history of or actual drug dependance. The prescription of lorazepam should a) be restricted for the treatment of states of restlessness and should b) normally be restricted to a duration of 14 consecutive days unless the patient´s condition requires longer treatment. No other additional psychotropic medication is allowed during the study period.

If patients are under current psychotropic medication while entering the study, this medication will be washed out during a period of 14 days according to the clinical standards of psychiatry and depending of the needs given by the previous used drug. This wash-out will be documented on a day-to-day base in the CRF. This wash-out scheme secures that no patient will be without medication at any time of this study.

Non-medicinal psychotropic treatment and non-psychotropic drugs for other medical conditions can be administered as usual. The investigator should instruct the patient to inform the investigator’s staff about any new medication taken during the study. All medications beside the study drugs as well as lorazepam and biperiden, psychotropic or non-psychotropic and all non-drug therapies (including blood transfusions) applied after the patient’s participation in the study must be reported on the CRF.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 25 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

8.3 Procedures for Monitoring Subject Compliance The investigator should instruct the patient to inform the investigator’s staff about any new medication taken during the study. All medications beside the study drugs as well as lorazepam and biperiden, psychotropic or non-psychotropic and all non-drug therapies (including blood transfusions) applied after the patient’s participation in the study must be reported on the CRF. There will be the following procedures for monitoring patients’ compliance recorded in the CRF of each patient:  Study drug compliance check in CWs 6 and 24 (visits 4 and 6): remaining capsules.  Concomitant lorazepam / biperiden medication check at days -1 till 0, 1 and in CWs 2, 4, 6, 12, 24 and 48 (visits 0-7): daily dose, start and stop date (or ‘ongoing’).  Lorazepam and biperiden compliance check in CWs 6 and 24 (visits 4 and 6): remaining tablets.  Concomitant psychiatric medication / treatment check at days -1 till 0, 1 and in CWs 2, 6, 24 and 48 (visits 0-2, 4, 6-7): dose, application, start and stop date (or ‘ongoing’), reason for use.  Concomitant nonpsychiatric medication / treatment check at days -1 till 0 and in CWs 6, 24 and 48 (visits 0, 4 and 6-7): used within 30 days prior to baseline or during the study, dose, application, start and stop date (or ‘ongoing’), reason for use.

9 Assessment of Efficacy

9.1 Specification of the Efficacy Parameters

9.1.1 Primary Endpoints  Change from baseline to CW 24 (visit 6) in the total score of SF-36 (interviewer version with a time frame of one week) and improvement of CGI (both measured by AUC based on logtime scale)

9.1.2 Secondary Endpoints  Subscores of SF-36 (AUC, logtime)  SWN-K  PSP (family member rating, rating by oneself, family member questionnaire)  PANSS

9.1.3 Adjunctive Secondary Outcome Measures (Efficacy Analyses)  CGI-S  CGI-matrix  Mini-ICF-Rating for Mental Disorders (Mini-ICF-P)  Trail Making Test (A and B)  “Regensburger Wortflüssigkeits-Test (RWT)”  “Buchstaben-Zahlen-Test”  “Verbaler Lern- und Merkfähigkeitstest (VLMT, A, C, D)”  “Mehrfachwahlwortschatztest (B)”  CNCM7  DISF-SR

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 26 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

9.2 Assessing, Recording and Analyzing of Efficacy Parameters Measurement of the primary endpoints SF-36 and CGI will be performed at baseline and in CW two, four, six, twelve, 24 and 48 (visit 0, 2-7, CGI-S at baseline and CGI-improvement thereafter). For each patient an individual AUC based on a logarithmic time scale will be calculated. The secondary endpoints SWN-K, PSP and PANSS as well as the adjunctive secondary outcome measures excepting “Mehrfachwahlwortschatztest (B)” will be collected at baseline and in CW six and 24 (visit 0, 4 and 6), the “Mehrfachwahlwortschatztest (B)” only at baseline (visit 0). Change from baseline to CW six (visit 4), CW six to CW 24 (visit 6) and baseline to CW 24 will be measured. The efficacy analyses of the primary and secondary endpoints will refer to the first 24 CWs. After the follow-up at CW 48 (visit 7) the primary endpoints will be analyzed for explorative purposes.

10 Assessment of Safety

10.1 Specification of Safety Parameters  Adverse events (AEs)  Drop-out rates between the groups  SAS / AIMS / BARS and sexual dysfunction changes from baseline to CW 24 (visit 6)  Metabolic side effects (from baseline to CW 24 (visit 6)):  BMI  Waist circumference  HbA1c  Fast blood glucose levels  Lipid profile changes (total cholesterol / LDL-cholesterol / HDL-cholesterol / triglycerides)  Other parameters of hematologic blood analysis  CRP  Serum levels of the respective study drug (olanzapine, quetiapine, aripiprazole, haloperidol, flupentixol)  Vital signs  ECG parameters

10.2 Assessing, Recording and Analyzing of Safety Parameters Safety analyses will be performed in all patients. BMI, waist circumference, SAS / AIMS / BARS and sexual dysfunction will be assessed at baseline and in CW two, four, six, twelve, and 24 (visit 0, 2-6), AEs and drop-out rates at baseline, day one, CW two, four, six, twelve, and 24 (visit 0-6); all these parameters will also be surveyed at follow-up (CW 48) or 24 CWs after premature termination of study participation. The blood safety analyses will be performed at baseline and in CW four and 24 (visit 0, 3 and 6). An ECG will be collected at baseline and in CW six and 24 (visit 0, 4 and 6). The serum drug level analyses will be performed in CW four and six (visit 4 and 6). Serum drug concentrations can additionally be measured in case of an SAE or if an additional measurement is indicated for other safety reasons. ------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 27 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

Measurements of the study drug serum concentrations are performed in CW four and six (visit 4 and 6). In order to avoid unblinding the results of these measurements will be forwarded to the investigators without naming the compound nor the exact concentration value. Instead, the concentration will be communicated as one of the following: - "below therapeutic concentration range" - "within therapeutic concentration range" - "above therapeutic concentration range" For this purpose, the concentrations measured are compared with the range information described in the Consensus Guidelines of the “TDM-Konsensgruppe der Arbeitsgemein- schaft für neuropsycho-pharmakologie und Pharmakopsychiatrie” (AGNP) as communicated by Prof. Dr. Hiemke (Mainz). The general examination consists of vital signs and cardiovascular measurements (blood pressure in sitting position and heart frequency), the blood safety analyses of hematology, HbA1c, fast blood glucose levels, liver enzymes (GOT / GPT / Gamma-GT), lipid profile (total cholesterol / LDL-cholesterol / HDL-cholesterol / triglycerides), CRP and creatinine and the serum level analyses of the serum levels of the respective study drug (olanzapine, quetiapine, aripiprazole, haloperidol, flupentixol). The efficacy analyses of the safety analyses will refer to the first 24 CWs. AEs will be analyzed by time of occurrence, duration, relation to treatment, grade, seriousness, consequences (intervention) and outcome and drop out cases by their reason. Parameters measured more than three times will be analyzed by AUC (logtime) and trend analysis, parameters with less measurements by pre-post-differences with respect to accessible intervals.

10.3 Adverse Events (AEs) An AE is the occurrence or worsening of any unwanted symptom or medical condition observed after the commencement of the study even if the event is not correlated to the study drug itself. A disease that has started before the study drug was applied is only defined to be an AE if it worsened after the first dose of the study drug was given. Results of laboratory examinations or tests are defined as AEs if they result in significant clinical signs or symptoms or a therapy has to be conducted. Thus, AEs can be revealed by the patient him/herself, mentioning a change in health condition, by physical examination or abnormal laboratory results. A non-directive questioning of the patient at every study visit should try to determine the existence of AEs. Each AE should be evaluated to determine:  the severity grade (mild, moderate, severe)  its relationship to the study drugs (certain, probable, possible, unlikely, not related, not to classify)  its duration (start and end dates, continuation until last visit)  following consequences (no consequences; study drug interrupted; study drug discontinued as a result of the AE; administration of concomitant medication; non- drug therapy; hospitalization as a result of AE)

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 28 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

A Serious Adverse Event (SAE) is defined as:  fatal  life-threatening  resulting in persistent or significant disability / incapacity  causing hospitalization or its prolongation for reasons other than: o observation or routine treatment of the studied indication, if not associated with any worsening in condition o a treatment (elective or pre-planned) for a pre-existing disease not referred to the study examination disease and not worsened since start of study drug o treatment on an emergency outpatient department for an event other than SAE and not resulting in hospital admission o social reasons  invalidity, congenital anomaly An event is medically relevant, if it can harm the patient or may require medical therapy (including surgical intervention) to prevent one of the findings given above. SAEs require ongoing control and have special reporting requirements: To ensure patient safety, every SAE occurring after the patient is randomized and until 24 CWs after the patient has stopped study drug application, will be reported to the coordinating investigator within 24 hours after learning of its occurrence. This applies without regard to suspicion of causality or not. Each recurrence, complications or further aggravation of the initial SAE must be reported as follow-up to the original SAE within 24 hours after the investigator was informed. All SAEs which occur at another time interval or which are considered completely unrelated to a previously reported SAE will be reported separately as a new event. All information about SAEs is recorded on the Serious Adverse Event Report Form (SAErF). The investigator must assess the suspected relationship to study drug application or to study procedures. Thereafter, he will send the signed SAErF by fax within 24 hours to the coordinating investigator. The original copy of the SAErF, together with the confirmation of successful fax transmission must be kept with the CRF at the study site. The follow-up information are sent by using a new SAErF clearly defining this report as a follow-up information to an already reported SAE (including the date of the initial report).The follow-up report is expected to contain information on resolving or continuation of the adverse effect and which therapeutic measures were applied. In addition the follow up report has to contain the information if the blinding was broken or not, and if the patient continues or has withdrawn from the study participation. If SAEs are noticed which are not documented in the actual version of the product information leaflet and which are suspected to be related to the study drug, the sponsor will immediately report this SAE to the German Health Authorities, the involved Ethics Committees and to the manufacturer. In addition, the sponsor will inform all investigators about this SAE. All AEs should be treated adequately. If required the administration of a study drug has to be interrupted or stopped. Treatment with concomitant medication according to the symptoms, accomodation of monitoring and assessments, hospitalization, or any other therapy, including surgical intervention has to be ascertained. An AE should be monitored until patient’s recovery and appropriate assessment has to be made as often as necessary. Changes in severity, the suspected relationship to the study drug, the interventions required to treat it, and the outcome must be recorded. All information about AEs will be listed in the Patient Informed Consent Form and should be discussed with the patient during the study as needed. All patients will have a telephone number to contact in case of emergence of AEs / SAEs.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 29 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

If clinical monitoring is required, the patient will be asked to return to the clinical department. Documentation of attempts to contact the patient should be recorded in the patient’s source documentation.

10.4 Follow-up of Subjects after AEs All AEs should be treated adequately. If required the administration of a study drug has to be interrupted or stopped. Treatment with concomitant medication according to the symptoms, accommodation of monitoring and assessments, hospitalization, or any other therapy, including surgical intervention has to be ascertained. An AE should be monitored until patient’s recovery and appropriate assessment has to be made as often as necessary.

11 Statistics

The statistical analyses will be performed by Prof. Dr. rer. nat. Dr. h. c. Jürgen Timm, KKSB Biometry, University of Bremen. The statistical procedures may be outlined as follows, detailed information is contained in the Statistical Analyses Plan.

11.1 Statistical Methods

11.1.1 General items Statistical analysis will be performed on the intention-to-treat (ITT) collective consisting of all randomized patients with at least one intake of study drug. Additionally, a sensitivity analysis will be performed on the per-protocol (PP) collective of all patients with treatment and with documentation of efficacy criteria in concordance with the study protocol. Patients with at least six weeks of treatment are classified as treated per protocol. A sensitivity analysis will be applied to investigate the different approaches for imputation of missing values. Details will be contained in the statistical analysis plan (see for example Molenberghs & Kenward 2007). An alpha adaption (see below) will be applied, as two primary criteria of efficacy will be used (patient and psychiatrist view, measured by SF-36 and CGI). All statistical tests will be two- sided. Details will be fixed in the statistical analysis plan prior to trial setup. Any item documented in the CRF will be analysed descriptively. Continuous measurements will be presented by tabulation of number, mean, standard deviation, range, median and inter quartile range. Categorical data will be tabulated by numbers and percent for each category. Tables will offer subgroup values for centres, drugs and strategies. The statistical analysis will be conducted using SAS.

11.1.2 Primary analysis of efficacy SF-36 and CGI are used as primary endpoints. SF-36 physical and mental scores will be added to provide a joint quality of life criterion. CGI-S will be used as baseline, CGI- improvement thereafter. Measurements at each visit are further integrated by AUC calculation. The time scale (weeks) will be logarithmically transformed before this procedure using 0 on the transformed scale as the baseline point. This procedure reflects results from prior trials showing that the change of conditions is smoothing out between the first weeks and the later time period of treatment. The AUC calculation will use the exact time point of each visit which might differ from the planned date. However, to ensure a constant overall

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 30 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

time interval the value for the final analysis will be taken at exactly 24 CWs using linear inter- or LOCF-extrapolation where necessary (see 11.5 for details). The AUC is used as target quantity of the statistical analysis as it constitutes a comprehensive quantifycation of the patient status over a 24-CW period. Calculating the AUC on the basis of a logarithmic time scale puts higher emphasis on the first part of the treatment period, which is supported by reported findings of distinct changes in the early study period, seen both from the psychiatrist’s as well from the patient’s perspective. The null hypothesis of no difference between the mean of patients treated with typical versus the mean of patients treated with atypical drugs will be tested at an overall significance level of 5% using a Bonferroni-Holm procedure for both SF-36 AUC as well as CGI AUC. The analysis will use ANOVA in case of homogeneous baseline values otherwise ANCOVA with the baseline value as a covariate and treatment group (five different drugs) as independent variable. ANCOVA is chosen as the analysis approach, because it allows a simple check of model assumptions together with the possibility, if necessary, of deriving data transformations (in a pilot phase) to establish the validity of model assumptions. ANCOVA also allows incorporating baseline values and treatment effects in an easily interpretable way. Scaling methods (either subtracting the baseline value from all subsequent values or dividing all subsequent values by the baseline value) may ignore (inadequately) the fact that also the initial value contains a random fluctuation component. Moreover, scaling by the ratio approach may generate a scaled quantity with undesirable distributional properties: if the initial scores were normally distributed, the ratio observed value / baseline either has a degenerate or a Cauchy distribution, which is not suitable for standard parametric test procedures. The linear contrast of typical versus atypical drugs will be computed using drug means, such that the null hypothesis is specified as contrast = 0. The contrast weights are specified as (-1/2, -1/2, 1/3, 1/3, 1/3), as there are two typical and three atypical drugs in the trial. Pilot studies will be examined in order to decide about the ANCOVA assumptions. In case of relevant deviations nonparametric alternatives will be preferred and accordingly defined in the statistical analysis plan prior to analysis.

11.1.3 Secondary analysis of efficacy Secondary endpoints and adjunctive outcome measures will be analysed using the same methods as the primary endpoints as far as adequate, but in an explorative manner only. AUC with a log(time) scale will be computed if measurements at each visit are planned. Otherwise post values will be analysed by ANCOVA, taking baseline value as covariate and drug group as independent variable followed by testing the contrast of typical versus atypical strategy. For each scoring system the specific method of scoring and analysis proposed in the original publications will be computed. Again nonparametric alternatives will be preferred and defined in the statistical analysis plan prior to analysis in case of relevant deviations from ANCOVA assumptions. A separate exploratory analysis of follow-up results will be done after the last patient has completed the first 48 CWs after enrolment.

11.1.4 Safety analysis Adverse events will be presented as case wise listing and tabulated by strategy, drug, time of onset and duration, type of event, body system, grade, seriousness, relation to treatment, counter measures and outcome. Kaplan-Meier curves and Cox proportional hazard regression model will be used to analyse time to adverse events and discontinuation of treatment for various reasons. Special analyses will cover drop-out rates between the two treatments groups, EPS (with SAS, AIMS, BARS), sexual dysfunction changes and metabolic data: BMI, waist circumference, HbA1c, fast blood glucose levels and lipid profile on a pre-post-difference approach using nonparametric methods (Kruskal-Wallis test for drug differences). The respective scores will be calculated in concordance with the original publications for these instruments. All safety analyses will be of exploratory character. ------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 31 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

11.1.5 Baseline characteristics The baseline characteristics age, sex, diagnosis, duration of disease and depression (item 6 of PANSS) will be analysed for homogeneity of strategy groups comparing patients randomised to typical versus atypical drug treatments. Inhomogeneously distributed baseline parameters will be incorporated into the primary analysis ANCOVA model for explorative purposes. Baseline characteristics of endpoints (primary as well as others) will be incorporated in the analysis of the respective endpoint using methods described above.

11.1.6 Additional analyses Regarding the primary endpoints patients with proper serum levels of the respective drug (according to the TDM study group of AGNP; Baumann et al. 2004) will be compared to those who do not meet this criterion. This analysis will be in explanatory means. Concomitant diseases and medication will be analysed descriptively. Explorative nonparametric analyses of association to efficacy and safety will be kept to a minimum defined by the statistical analysis plan after analysing pilot data. Pearson correlation coefficients are calculated to explore the association between physician’s rating of psychopathology (CGI-S, PANSS) and patient’s rating of subjective well-being and quality of life scores (SF-36, SWN-K) including subscales. Further analysis will cover the interaction between safety and efficacy items, as a strong interaction with the primary endpoints may be expected.

11.1.7 Interim and subgroup analysis No interim analysis concerning efficacy criteria is provided. However, analysis of recruitment rates in total, by centres and comparative pairs actually chosen will be established. Enrolment and screening logs will be analysed continuously. Quotients of enrolled divided by eligible patients will be calculated, as well as forecasts of total enrolment within the study period. Independently the Data Monitoring and Safety Board (DMSB) may decide about special interim analysis plans to be discussed in closed sessions and only available for the DMSB. Subgroup analysis of efficacy and safety parameters is planned for centres, drugs and the baseline characteristics listed above. The subgroup analysis will consist of descriptive statistics. Patients with missing values for a specific criterion will be excluded from the respective subgroup analysis. No confirmative analysis of subgroups will take place.

11.2 Sample Size and Power Sample size calculation bases on an alpha level of 5% and a power of 80%. As two primary criteria are involved, an alpha adaption has to be applied. An alpha level of 2.5% for each primary endpoint is used in the sample size calculation (conservative approach). The guiding idea of the sample size calculation is to carefully avoid underpowering of this trial by conservative assumptions reflecting limited knowledge about specific details of parameter levels and distributions in question. This results in a slightly increased sample size, which, however, is useful in the case that ANCOVA model assumptions might turn out to be violated and the statistical analysis has to switch to alternative nonparametric procedures. Information about parameters relevant for the sample size calculation was obtained from pilot studies and literature data, as documented below.

11.2.1 Patients’ Assessment (Quality of Life, SF-36 Measurements) The German Normative Sample (N=2773) provides standard deviations of 10.24 (physical) and 8.14 (mental) for the total SF36 score. Standard deviations for schizophrenic patients do not differ very much: Reine et al. 2005 found 8.2 and 11.1 (207 patients), respectively.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 32 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

Rosenheck et al. 2003 calculated 10.2 / 12.2 for 309 patients using the short version of this quality of life instrument and Messer et al. 2007 reported 9.9 / 10.6 scores for the SF12 (N=799). Consequently we assumed a standard deviation of 9.7 and 11.1 for the SF36, respectively (square root of the weighted mean of variances). The primary criterion of patient’s quality of life assessment is the sum of the mental and the physical subscale. The normative sample and diverse studies show a significant correlation between these subscores. For the sample size calculation a prudent assumption of a correlation coefficient of 0.9 between the subscores was used. With the resulting variance- covariance matrix (94.58, 96.93 / 96.93, 122.64) an expected standard deviation of 20.28 was obtained, not far from the worst case of a 1.0 correlation, which would have resulted in a standard deviation of 20.80. The investigators defined a treatment group difference of 5 to 10 scores as relevant for both subscales. Taking the smaller value of these proposals, a relevant difference of 5 for each subscale seems be adequate, which yields a relevant difference of 10 for their sum. A formal support for this definition is the approach to take half of the standard deviation as relevant difference (see for example Naber et al. 2005). In this trial the main interest does not focus on the difference between two individual drugs, but on the difference between the means of the strategy groups (typical versus atypical drugs). As the mean difference between strategy groups is expected to show less variation than the mean difference that could be attributed to an individual drug, a moderately smaller difference for strategy means than for drug means was implemented in the sample size calculation. A difference of 8 (80% of 10) is used as the relevant difference.

11.2.2 Psychiatrists’ Assessment (CGI) Standard deviations of 1.0 for CGI-S or CGI-improvement scores are documented by Lambert et al. 2006 for 2960 patients. CGI standard deviations of 0.75 were reported by Rosenheck et al. 2003 (N=309), of 1.12 by Schooler et al. 2005 (N=527), of 0.93 by Liebermann et al. 2005a (N=1460), 0.95 by Schimmelmann et al. 2007 (N=63) and 1.35 by Naber et al. 2005 (N=99). Using this information, the sample size calculation is based on a standard deviation of 0.99 for the CGI score (square root of the weighted mean of variances). The investigators defined a score difference of 0.5 as relevant for this trial, which again is compatible with the approach of taking half of the standard deviation as relevant difference. Again a 20% reduction of this value was implemented in sample size calculation, taking into account that the mean of strategies and not the mean of drug groups is the primary criterion of efficacy in this trial. The resulting value of the relevant difference for strategy means is 0.4.

11.2.3 Integration of Single Values into AUC A logarithmic time scale provides similar distances between visits, thus making the AUC nearly equal to the mean of the single measurements multiplied by a constant scale factor. Hence it seems sufficient to calculate the sample size for the AUC mean. The more severe problem, however, is to quantify the correlation structure for consecutive values from the same patient. Empirical data about correlations between consecutive measurements of SF- 36 and CGI are rare in the appropriate literature. In the case of independent values the standard deviation of the mean is s/sqrt-(5) as five visits are integrated in the AUC (s=standard deviation of single measurements). For highly correlated consecutive values the standard deviation of their mean will nearly equal the standard deviation s of the single measurements. As a precaution against under powering, the latter value is taken for the sample size calculation.

11.2.4 Statistical Method to be Used An ANCOVA with test for linear contrasts (typical versus atypical drugs) is planned for both primary criteria.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 33 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

As a consequence of the design of this trial, unequal numbers of patients in the drug groups have to be taken into account. Unequal group sizes increase the sample size needed. If selection effects with respect to specific combinations and comparative pairs are neglected, the rates of patients allocated to drug groups will be ¼, ¼, 1/6, 1/6, 1/6 depending on the strategy group (1/4 per typical and 1/6 per atypical drug). However there is evidence that some investigators might tend to avoid haloperidol in certain situations after considering the specific diagnosis and medical history of the patient in question. This will amplify the imbalance of drug groups. Considering the worst case of avoiding haloperidol as far as possible, the number of patients in the haloperidol group will be decreased as follows. There are 3 out of 15 pair combinations with haloperidol as part of both comparative pairs. In these three cases the investigator is unable to omit haloperidol. These combinations are (1,2), (1,3) and (2,3) in the scheme above. They include a proportion of 20% (=3/15) of all combinations. As the random generator will decide for the atypical strategy in 50% of these combinations the resulting rate for the haloperidol group is 10%. The rate of flupentixol will simultaneously increase to 40%, as the sum of all typical drugs is allocated with a 50% chance. For this “worst case”, the relative sizes of the drug groups are 10%, 40%, 16.667%, 16.667%, 16.667% of the respective strategy group.

11.2.5 Sample Size Calculation The resulting parameters of sample size calculation are

SF-36 AUC CGI-improvement AUC Level of significance 2.5% 2.5% Sides of testing 2 2 Power 80% 80% Number of drug groups 5 5 Contrast to be detected 8 0.4 Scale factor D 0.716 0.716 Common standard deviation 20.28 0.99 Effect size 0.551 0.564 N as multiple of n1 10 10

Resulting sample size (total) 316 301

Significant drop out rates are common in this patient collective. The following publications have been analysed for drop out rates at six months: Jones et al. 2006 18% out of 227 patients, Schooler et al. 2005 62% out of 400, Csernansky et al. 2002 46% out of 365, Rosenheck et al 2003 43% out of 309, Liebermann et al. 2005 a and b between 40 and 58% (total number of patients 1493), Lambert et al. 2006 34% out of 394 and 29% out of 2492 patients, Kahn et al. 2008 498 Patients with rates between 65 and 29%. The weighted mean of these dropout rates is 40%. As the size of the dropout rate may be crucial for the trial the investigators decided to use a cautious estimate of 50% for the sample size proposal. This approach doubles the number of patients needed to 632. Because of the complex structure of the trial design a balanced design needs a sample size that may be divided by 30 (15 comparative pairs multiplied by two strategies). Thus the result of these considerations is a total sample size of N = about 630. The sample size calculation has been computed with nQuery Advisor © version 7.0.

11.2.6 Feasibility of Recruitment There are approximately 15 participating centres. All participating centres are psychiatric hospitals with large catchment areas. Each centre has calculated to be feasible and most

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 34 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

centres agreed to recruit at least about 80 patients (Osnabrück about 50, Hamburg and Hannover about 60). The average number of admissions with schizophrenia per centre is about 450 patients / year, total 5.400 in 18 months. Most of them will meet the inclusion and exclusion criteria of this study. It is estimated that about an eights of these will be willing to participate in this study. The applicants are aware of a high drop-out rate in schizophrenia studies. Thus for power analyses a drop-out rate of 50 % was calculated.

11.3 Level of Significance The null hypothesis of no difference between the mean of patients treated with typical versus the mean of patients treated with atypical drugs will be tested at the total significance level of 5% for both SF-36 AUC as well as CGI-improvement AUC. A Bonferroni-Holm procedure will be applied to deal with this multiple testing situation avoiding too conservative settings.

11.4 Criteria for the Termination of the Trial The trial may be terminated if  the Data Monitoring and Safety Board (DMSB) advices a termination because of severe safety problems.  the DMSB, the sponsor or regulatory authorities observe significant incompliance with GCP, legal regulations or study protocol.  recruiting rates are too small to reach the preplanned number of cases within appropriate time. Analysis of enrollment and screening logs will be performed to offer detailed information about this point.  the financial aid of the BMBF would be stopped or shortened in a relevant amount.  severe problems in study organization and administration occur. Trial termination for single centers due to analogous reasons are possible (see 13 for details of quality assurance).

11.5 Procedures for Missing, Unused and Spurious Data Missing values (MV) for efficacy and safety parameters will be treated as follows: In the case of AUC-calculation MV are ignored as long as there exists a later value within the interval of interest (this is equivalent to an interpolation using the logtime scale). If an endpoint at 24 CW is missing, but there is a later value an interpolation between the last available value for t<24 CW and the first value thereafter is imputed at CW 24. If the endpoint at CW 24 is missing but there is no later value the LOCF method will be used imputing a limiting value for the interval of interest. A sensitivity analysis will be performed analyzing the impact of these and other favourable imputations. This procedure is especially relevant for the primary criteria of efficacy but will be applied to secondary and safety parameters as far as possible. Some secondary criteria result in only three or less values during the study course. In these cases of exploratory analysis there is no imputation planned but a careful discussion in the statistical report. MV within a scoring system (i.e. questions without answer etc.) will be treated as prescribed in the respective instruction document. If there will be unused and spurious data these will be documented and discussed in the statistical report.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 35 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

11.6 Procedures for Deviations from the Original Statistical Plan Deviations from the original statistical plan will be kept as small as possible. They will be detailed documented and discussed in a separate paragraph of the statistical report. No deviations from the SAP for the deductive analysis of the primary criteria after code breaking are allowed.

11.7 Collectives for Analyses The randomized patient population will consist of all patients, who received a randomization number. The main analysis of efficacy will be performed on the intention-to-treat (ITT) collective consisting of all randomized patients with at least one intake of study drug. Additionally, a sensitivity analysis will be performed on the per-protocol (PP) collective of all patients with treatment and with documentation of efficacy criteria in concordance with the study protocol. Patients with at least six CWs of treatment are classified as treated per protocol. If any significant protocol deviations are noticed, the patient or data from specific patient visits or evaluations may be excluded from the PP analysis. The criteria and the determination of the clinically relevant protocol deviations together with the corresponding patient specific identification of data to be excluded from the PP analysis will be data-based and finalized prior to locking the database and unmasking of treatment codes. All safety data will be analyzed using the safety population. The safety population will consist of all randomized patients with at least one intake of study drug. The statement that a patient had no AEs also constitutes a safety assessment. Patients will be analyzed according to treatment received.

12 Direct Access to Source Data / Documents A central rater training and additional site initiation visits at any study site will be held by the KKSB' s study team. At these occasions, all necessary information on protocol, CRFs, and SAE reporting will be given and the respective forms will be reviewed with all investigators and their staff. All personnel of the investigator's site integrated in the study have to be designated in the Study Site Personnel Form and only personnel designated as such is allowed to enter the study information into the CRFs. During the study, a monitor of the KKSB (Institut für Pharmakologie) will visit the study site in regular time intervals, approximately every 4-6 weeks. At these visits the monitor will review CRFs by source data verification. The investigator must give the monitor access to all relevant source documents. Members of the study site personnel shall be present at these occasions to assist the monitors. The monitors will document the presence of all relevant documents, check the adherence to the criteria for inclusion and exclusion of patients, handling of SAE, and, in sense of source data verification, the record of data used for primary and secondary and safety variables. Additionally PI's study team members and members of KKSB Biometry (data management) will review the CRFs for completeness and accuracy. In the case of missing data, obviously false or implausible data entries the site personnel will be instructed to enter all necessary corrections or additions. The adherence to Good Clinical Practice (GCP) will be monitored, too.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 36 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

13 Quality Control and Quality Assurance

A DMSB will be formed, which will consist, according to GCP, of five scientific members entirely independent of the sponsor, the coordinating investigator and the medical institutions and not involved in any part of the study. To warrant complete insight of DMSB members into the study, two additional, however non-voting, members will participate in the DMSB meetings who are involved in the study. The function of the DMSB will be to monitor and supervise the progress of the trial (including the safety data and the critical efficacy endpoints at intervals), to review relevant information from other sources, to ensure adherence to protocol, to consider interim analyses, and to provide the sponsor and funding organization with information and advice. To ensure patient safety, every SAE occurring after the patient is randomized and until 24 CWs after the patient has stopped study drug application, will be reported to the coordinating investigator within 24 hours of learning of its occurrence. This applies without regard to suspicion of causality or not. Each recurrence, complications or further aggravation of the initial SAE must be reported as follow-up to the original SAE within 24 hours after the investigator was informed. All SAEs which occur at another time interval or which are considered completely unrelated to a previously reported SAE will be reported separately as a new event. All information about SAEs is recorded on the Serious Adverse Event Report Form (SAErF). The investigator must assess the suspected relationship to study drug application or to study procedures. Thereafter, he will send the signed SAErF by fax within 24 hours to the coordinating investigator. The original copy of the SAErF, together with the confirmation of sucessful fax transmission must be kept with the CRF at the study site. The follow-up information is sent by using a new SAErF clearly defining this report as a follow-up information to an already reported SAE (including the date of the initial report).The follow-up report is expected to contain information on resolving or continuation of the adverse effect and which therapeutic measures were applied. In addition the follow up report has to contain the information if the blinding was broken or not, and if the patient continues or has withdrawn from the study participation. If SAEs are noticed which are not documented in the actual version of the product information leaflet and which are suspected to be related to the study drug, the sponsor will immediately report this SAE to the German Health Authorities, the involved Ethic Committees and to the manufacturer. In addition, the sponsor will inform all investigators about this SAE. On monitoring adverse side effects, we will pay special attention to the metabolic syndrome, since the comorbidity of mental illnesses and the metabolic syndrome is emerging as an important public health issue. The prevalence of the metabolic syndrome is clearly increased in patients with schizophrenia compared to the general population (Toalson et al. 2004). Much of this increased risk can be explained by lifestyle factors associated with the disease such as high caloric intake, smoking habits, lack of exercise, and restricted access to health care providers. The use of several of the so-called atypical neuroleptics is associated with weight gain, diabetes and an atherogenic lipid profile. The atypical antipsychotic olanzapine seem to have the strongest effects on weight gain and also involve an increased risk for diabetes, while a moderate level of weight gain is observed with the atypical antipsychotic drug quetiapine (Newcomer 2005). Unwanted weight gain is one of the main reasons for schizophrenic patients to discontinue atypical antipsychotic treatment. In our study, the clinical examination, the anamnesis, and laboratory results will help to identify patients with high risk for weight gain and metabolic syndrome under antipsychotic treatment. We want to help clarify the clinical predictors of weight gain and metabolic disturbances in antipsychotic- treated patients. ------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 37 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

14 Ethics

A detailed consideration of all possible harms and positive effects of trial participation for the patients has been carried out prior to formulation of this protocol. All investigational drugs are well established and several clinical trials ensure their efficacy and safety with respect to the patient population and disease in the focus of this trial. The special design of this trial enables the investigators to meet the individual patient needs in spite of randomization in an unusual extent. Precaution against individual risks due to trial treatment is achieved by specific measurements described above. Summing up the investigators are sure that the trial yields a positive gain for the participators as well as important results applicable for further treatment decisions of schizophrenia. The study will be conducted according to the standards of the guideline for the Good Clinical Practice (CPMP/ICH/135/95), “Verordnung über die Anwendung der Guten Klinischen Praxis bei der Durchführung von klinischen Prüfungen mit Arzneimitteln zur Anwendung am Menschen (“GCP-Verordnung”) vom 9. August 2004, zuletzt geändert durch Artikel 4 der Verordnung vom 3. November 2006”, the ethical convention of the revised declaration of Helsinki of the “Weltärztebundes” (Seoul 2008) and the German Medicines Law and Data Protection Act. The study must not be initiated before permission of the Federal Institute for Drugs and Medical Devices (BfArM) and the responsible ethical committee have been received. The ethical tenability for conducting this study is given since all patients will receive an active therapy. An independent Data Monitoring and Safety Board will supervise the study to warrant individual and general patient safety. Insurance will be set up.

15 Data Handling and Record Keeping

According to GCP all investigators will store the source documents for each patient in the study. These source documents will contain all information such as case and visit notes (including all medical records) and also the demographic data. All information noted in the CRFs must by traceable to the respective source data. Other data which can be recorded directly on the CRFs will be defined before study start, and they will be accepted as the source data. In addition, at all study sites the original of the informed consent form signed by the patient has to be maintained while a signed copy must be handed out to the patient. The monitors will document the presence of all relevant documents, check the adherence to the criteria for inclusion and exclusion of patients, handling of SAE, and, in sense of source data verification, the record of data used for primary and secondary and safety variables. The CRFs are stored at the University of Bremen, one copy being retained at the investigational site. When the CRFs arrive at the University of Bremen, their receipt is recorded and stored according to GCP. Data from the CRFs are entered into the study database by members of the KKSB Biometry following the internal standard operating procedures. Subsequently, the entered data are systematically checked by Data Management staff at the KKSB Biometry, using error messages printed from validation programs and database listings. If data errors are obvious they can be corrected by the KKSB Biometry personnel following established obvious corrections guidelines. Other errors or missing data are entered on Data Query Forms, which are sent to the investigators’ site for correction or addition. The signed originals of the Data Query Forms and the completed forms returned from the study site are stored together with the CRFs at the investigator’s site, and a copy is sent to the KKSB

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 38 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

Biometry where the corrections and additions will be entered into the database. A quality control audit of 10% of all data in the database is made by the staff of the KKSB Biometry prior to locking the database. AEs will be coded using the Medical Dictionary for Regulatory Activities (MeDRA). All protocol violations will be determined for the Treatment Period. Thereafter, the database for the Treatment Period will be declared to be accurate and will be locked. Not earlier than at that time point, the coding (allocation of the patients to treatment) may be unmasked for data analysis. Changes of the main database are not allowed after that time, unless it is agreed upon in written form, between the Head of the KKSB Biometry and the PI. Such changes will be documented in the statistical report and analysis will be done with and without these changes. Details about data handling will be defined in the Data management plan (DMP).

15.1 Safety data To ensure patient’s safety, every SAE occurring after the patient is randomized and until four weeks after the patient has stopped study participation, will be reported to the coordinating investigator within 24 hours of noticing of its occurrence. This applies without regard to suspicion of causality or not. SAEs experienced later than four weeks after the patient has stopped to participate must be reported to the coordinating investigator as well, independent of whether the investigator suspects a causal relationship to the study drug or not. In this case, in contrast, the time lag between observation and report to the coordinating investigator, may be up to seven days. Each recurrence, complications or further aggravation of the initial SAE must be reported as follow-up to the original SAE within 24 hours after the investigator was informed. All SAEs which occur at another time interval or which are considered completely unrelated to a previously reported SAE will be reported separately as a new event. All information about SAEs is recorded on the Serious Adverse Event Report Form (SAERF). The investigator must assess the suspected relationship to study drug application or to study procedures. Thereafter, he will send the signed SAERF by fax within 24 hours to the coordinating investigator. The original copy of the SAERF, together with the confirmation of successful fax transmission must be kept with the CRF at the study site. The follow-up information is sent by using a new SAERF clearly defining this report as a follow-up information to an already reported SAE (including the date of the initial report). Reports on recurrence, complications or further aggravation of the initial SAE must be sent to the coordinating investigator clearly marked as follow-up to the original SAE regardless of when it occurs. The follow-up report is expected to contain information on resolving or continuation of the SAE, if there was any medical treatment and, in this case, which therapeutic measures were applied. In addition the follow-up report has to contain the information if the blinding was broken or not, and if the patient continues or has withdrawn from the study participation. If SAEs are noticed which are not documented in the actual version of the Product Information Leaflet (in German: “Fachinformation”) and which are suspected to be related to the study drug, the sponsor will immediately report this SAE to the German Health Authorities, to the Ethics Committees and to the manufacturer. In addition, the sponsor will inform all investigators about this SAE.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 39 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

16 Financing and Insurance

The study will be funded by research funds of the Federal Ministry of Education and Research (BMBF). There is no other pharmaceutical or commercial sponsor of this multicenter trial (“sponsor” according to GCP and the German Drug Legislation). The study medication will be purchased (haloperidol, quetiapine, and placebo) or be provided, without restriction, by Bristol-Myers Squibb (aripiprazol), Lundbeck (flupentixol) and Lilly (olanzapine). Participants will be insured by special police of  Allianz Versicherungs-AG (Königinstr. 28, 80802 München, Telefon: 01802 / 10 01 17, Fax: 01802 / 400-102, E-Mail: [email protected]) for all health impairments and  SV SparkassenVersicherung (70365 Stuttgart, Telefon: 0180 / 333 9 333, Fax: 0180 / 333 9 888, E-Mail: [email protected]) for all travel accidents.

17 Publication Policy

Both design and results of the study will be completely published irrespectively of the outcome in an international peer-reviewed scientific journal. Besides the main publication (primary and secondary endpoints) a subset of publications is planned on additional topics, e.g. secondary outcome variables: drop-out rates between the groups, cognition and psychopathology, sexual side effects, EPS, metabolic data. Additionally, analyses of the performances of single substances might be possible.

18 Supplements

18.1 Persons Authorized to Sign the Protocol (Amendments) for the Sponsor  Prof. Dr. med. Gerhard Gründer  PD Dr. med. Martin Heinze  Prof. Dr. med. Bernd Mühlbauer  Prof. Dr. med. Eckart Rüther  Prof. Dr. rer. nat. Dr. h. c. Jürgen Timm

18.2 Sponsors’ Medical Experts  Prof. Dr. med. Gerhard Gründer, Klinik für Psychiatrie und Psychotherapie am Universitätsklinikum Aachen, Pauwelsstraße 30, 52074 Aachen, Tel. 0241 / 8089821  Prof. Dr. med. Andreas Heinz, Klinik für Psychiatrie und Psychotherapie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Tel. 030 / 450517001  PD Dr. med. Martin Heinze, Behandlungszentrum Mitte / West für Psychiatrie, Psychotherapie und Abhängigkeit, Klinikum Bremen-Ost gGmbH, Züricher Str. 40, 28325 Bremen, Tel. 0421 / 4081363  Prof. Dr. med. Bernd Mühlbauer, Institut für Pharmakologie, Klinikum Bremen-Mitte, St.- Jürgen-Str.1, 28177 Bremen, Tel. 0421 / 4975352

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 40 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

 Prof. Dr. med. Eckart Rüther, p.A. Kompetenzzentrum für Klinische Studien, Universität Bremen, Am Fallturm 1, TAB, 28359 Bremen, Tel. 089 / 51605556  Prof. Dr. rer. nat. Dr. h. c. Jürgen Timm, Kompetenzzentrum für Klinische Studien Bremen (KKSB) Biometrie, Am Fallturm 1, TAB, 28359 Bremen, Tel. 0421 / 2188977

18.3 Qualified Physician  PD Dr. med. Martin Heinze (Behandlungszentrum Mitte / West für Psychiatrie, Psychotherapie und Abhängigkeit, Klinikum Bremen-Ost gGmbH, Züricher Str. 40, 28325 Bremen, Tel. 0421 / 4081363) is responsible for all trial-site related medical decisions.

18.4 Other Medical Departments Involved in the Trial  Prof. Dr. rer. nat. Dr. h. c. Jürgen Timm, Kompetenzzentrum für Klinische Studien Bremen (KKSB) Biometrie, Am Fallturm 1, TAB, 28359 Bremen  Prof. Dr. med. Bernd Mühlbauer, Zentrum für Spezielle Analytik und Medizinische Diagnostik, Klinikum Bremen-Mitte, St.-Jürgen-Str.1, 28177 Bremen  Professor Dr. med. Thomas Schulz, Zentrum Laboratoriumsmedizin, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625 Groß-Buchholz, Hannover  Prof. Dr. med. Dr. h.c. Michael Oellerich, Abteilung Klinische Chemie, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075 Göttingen  Prof. Dr. med. Wolfgang Gaebel, Klinisches Labor, Rheinische Kliniken Düsseldorf, Bergische Landstr. 2, 40629 Düsseldorf  Prof. Dr. med. Prof. h. c. Axel Gressner, Institut für Klinische Chemie und Pathobiochemie sowie Klinisch-Chemisches Zentrallaboratorium, Universitätsklinikum Aachen, Pauwelsstraße 30, 52074 Aachen  Prof. Dr. med. Rudolf Tauber, Institut für Laboratoriumsmedizin und Pathobiochemie, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin  Prof. Dr. med. Mariam Klouche, Prof. Dr. med. Gregor Rothe, Bremer Zentrum für Laboratoriumsmedizin GmbH, Friedrich-Karl-Str. 22, 28205 Bremen  Prof. Dr. med. Sören Gatermann, Institut für Medizinische Mikrobiologie, Ruhr-Universität Bochum, Westring 28-30, 44777 Bochum / Dres. Dr. med. Dipl.-Chem. Doris Bachg, Dr. med. Uwe Haselhorst, LADR Medizinisches Versorgungszentrum Dres. Bachg, Haselhorst & Kollegen Recklinghausen – Dortmund GbR, Berghäuser Straße 295, 45659 Recklinghausen.  Prof. Dr. med. Christoph Wagener, Institut für Klinische Chemie / Zentrallaboratorien, Universitätsklinikum Eppendorf, Haus Ost 26, Martinistr. 52, 20246 Hamburg  Prof. Dr. rer. nat. Dr. med. Wilfried Bautsch, Institut für Mikrobiologie, Immunologie und Krankenhaushygiene, Städtisches Klinikum Braunschweig gGmbH, Celler Straße 38, 38114 Braunschweig  Dr. med. Michael Heins, Institut für Laboratoriumsmedizin, Mikrobiologie, Haemostaseologie und Transfusionsmedizin, Marienhospital Osnabrück, Bischofsstraße 1, 49074 Osnabrück

18.5 Products used as investigational drugs  AstraZeneca. Seroquel Prolong® Retardtabletten, Active pharmaceutical ingredient: Quetiapine.  Lundbeck Ltd., Milton Keynes, MK7 8LG, United Kingdom Depixol® tablets 3 mg, . Active pharmaceutical ingredient: Flupentixol. Marketing authorisation number PL 0458/0076.  Bristol-Myers Squibb / Otsuka Pharmaceuticals. Abilify® Tabletten, Active pharmaceutical ingredient: Aripiprazole.  TEVA UK Limited (United Kingdom). Haloperidol® 1.5 mg Tablets, Active pharmaceutical ingredient: Haloperidol. Marketing authorisation number PL 00530/0370  Lilly Deutschland GmbH. Zyprexa®, Active pharmaceutical ingredient: Olanzapine.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 41 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

18.6 DMSB Members The chair of the DMSB will be held by Dr. med. Eckermann (“Bezirkskrankenhaus Kaufbeuren”) who is member of the panel on adverse side effects of the “Arzneimittelkommission der Deutschen Ärzteschaft”. One of the DMSB members is a biometrical expert (Prof. Wegscheider, “Universität Hamburg”). Prof. Möller (“Ludwig- Maximilians-Universität München”) is a renowned psychopharmacologist. Both, Prof. Hiemke (“Johannes Gutenberg-Universität Mainz”) and Prof. Haen (“Universität Regensburg”) are, as is Dr. Eckermann, members of the TDM-group of the “Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP)” and connected to the “Institut für Arzneimittelsicherheit in der Psychiatrie (AMSP)”.

------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 42 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

19 References to Literature

Anon. Drugs & Therapy Perspectives. November 28 1994; 4:7-8 Ayd FJ Jr. Haloperidol: twenty years' clinical experience. J Clin Psychiatry 1978; 39:807-814. Balant-Gorgia AE, Balant LP, Genet C, et al. Comparative determination of flupentixol in plasma by gas chromatography and radioimmunoassay in schizophrenic patients. Ther Drug Monit 1985; 7:229-235 Balestrieri M, Giorali G, Mazzi M, Bellantuono C. Performance of the Italian version of the Subjective Well-being under Neuroleptic (SWN) scale in schizophrenic outpatients. Pharamacopsychiatry 2006; 39: 81-84 Baumann B, Hiemke C, Ulrich S, Gaertner I, Rao ML, Eckermann G, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Riederer P, Zernig G. The AGNP-TDM expert group consensus guidelines: Therapeutic Drug Monitoring in Psychiatry. Pharmacopsychiatry 2004; 37: 243 – 265Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second- generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004; 161: 414-425 Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004; 161: 414-425 Csernansky JG, Mahmoud R, Brenner R; Risperidone-USA-79 Study Group. A Comparison of risperidone and haloperidol for the prevention of replase in patients with schizophrenia. N Engl J Med 2002; 1: 16-22 Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003; 60: 553-564 Elkes J, Elkes C. Effect of chlorpromazine on the behaviour of chronically over-active psychotic patients. BMJ 1954: 560-565 Gaebel W, Falkai P, Weinmann S, Wobrock T. Behandlungsleitlinie Schizophrenie. Reihe: S3 Praxisleitlinien in Psychiatrie und Psychotherapie, Band 1. DGPPN (Hrsg.) 2006, XVI, 288 S; ISBN: 978-3-7985-1493-5 Green B. Focus on quetiapine. Curr Med Res Opin 1999; 15(3):145-151 Fulton B and Goa KL. ICI-204,636: an initial appraisal of its pharmacological properties and clinical potential in the treatment of schizophrenia. CNS Drugs 1995; 4(1):68-78 Jeste DV, Lacro JP, Bailey A, Rockwell E, Harris MJ, Caligiuri MP. Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc 1999; 47: 716-719 Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079-1087 Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, Gheorghe MD, Rybakowski JK, Galderisi S, Libiger J, Hummer M, Dollfus S, López-Ibor JJ, Hranov LG, Gaebel W, Peuskens J, Lindefors N, Riecher-Rössler A, Grobbee DE; EUFEST study group. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomized clinical trial. Lancet 2008; 371: 1085-1097 Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-796 Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA; CATIE Investigators; Neurocognitive Working Group. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64: 633-647 Kinon BJ, Lieberman JA. Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology 1996; 124: 2-34 Lambert M, Schimmelmann BG, Naber D, Schacht A, Karow A, Wagner T, Czekalla J. Prediction of Remission as a Combination of Symptomatic and Functional Remission and Adequate Subjective Well-Being in 2960 Patients With Schizophrenia. J Clin Psychiatry 2006; 67: 1690-1697 Lawler CP, Prioleau C, Lewis MM, et al. Interactions of the novel antipsychotic aripiprazole (OPC- 14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999; 20(6):612-627 ------Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 43 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------

Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005a; 353: 1209-1223 Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS, Keefe RS, Green AI, Gur RE, McEvoy J, Perkins D, Hamer RM, Gu H, Tohen M; HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005b; 62: 361-370 Naber D, Moritz S, Lambert M, Pajonk F, Holzbach R, Mass R, Andresen B. Improvement of schizophrenic patients´ subjective well-being under atypical antipsychotic drugs. Schiz Res 2001; 50: 79-88 Naber D, Riedel M, Klimke A, Vorbach EU, Lambert M, Kühn KU, Bender S, Bandelow B, Lemmer W, Moritz S, Dittmann RW. Randomized double blind comparison of olanzapine vs. clozapine on subjective well-being and clinical outcome in patients with schizophrenia. Acta Psychiatr Scand 2005; 111: 106-115 Newcomer JW. Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry 2007; 68 Suppl 4: 8-13 Rosenheck R, Perlick D, Bingham S, Liu-Mares W, Collins J, Warren S, Leslie D, Allan E, Campbell EC, Caroff S, Corwin J, Davis L, Douyon R, Dunn L, Evans D, Frecska E, Grabowski J, Graeber D, Herz L, Kwon K, Lawson W, Mena F, Sheikh J, Smelson D, Smith-Gamble V; Department of Veterans Affairs Cooperative Study Group on the Cost-Effectiveness of Olanzapine. Effectiveness and cost of olanzapine and haloperidol in the treatment of schizophrenia: a randomized controlled trial. JAMA 2003; 290: 2693-2702 Schimmelmann BG, Conus P, Cotton S, McGorry PD, Lambert M. Pre-treatment, baseline, and outcome differences between early-onset and adult-onset psychosis in an epidemiological cohort of 636 first-episode patients. Schizophr Res 2007; 95: 1-8 Schooler N, Rabinowitz J, Davidson M, Emsley R, Harvey PD, Kopala L, McGorry PD, Van Hove I, Eerdekens M, Swyzen W, De Smedt G; Early Psychosis Global Working Group. Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. Am J Psychiatry. 2005 May; 162: 947-953 Snyder SH. Dopamine receptors, neuroleptics and schizophrenia. Am J Psychiatry 1981; 138:460-464 Stroup TS, Alves WM, Hamer RM, Lieberman JA. Clinical trials for antipsychotic drugs: design conventions, dilemmas and innovations. Nat Rev Drug Discov 2006; 5: 133-146