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Request For The Approval For The Use Of Human Subject~in Rese rh Healt~ an.dBiologi~al Sciences

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Instztutlonal Revzew Board

Version 2/2001 Project Title:

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Efficacy and Tolerability of Olanzapine, Quetiapine <co ~ -t,-t,~ and Risperidone in the Treatment of First Episode sz vZ1. Psychosis: A Randomized Double Blind 52-Week
Comparison -The Cafe Study

Including middle initial and highestearneddegree

Principal Investigator:

Stephen C. Olson,M.D. 612.273.976

3 Pag~r or Cell Phone:

TelephoneNumber: Fax:

612.273.9779
University Fairview Other:

Department Name:
Mailing Address:

Department of Psychiatry 2 West Building/FUMC-Riverside 2450 Riverside Avenue Minneapolis, Minnesota 55454

E-mail Address:

olson403@umn.edu

:~,",:=o"...;;

If Principal Investigator is faculty or staff, a Department bead signature is required.

As Department Head, I acknowledge that this research is in keeping with the standards set by my department and I assure that the Principal Investigator has met all departmental requirements for review and a roval of this research.

~. Charles Schulz, M.D. -11.19.01

Name of Departm~tHead, or D~ector of Research Fairvie~ I Date
Date

Co-Investigators responsible for, or working on this projectshouldbe listed below. Include any individual who will haveresponsibilityfor the consent process, direct data collection from subjects,or follow-up. If therearemorethantwo Co-Investigators, please _attach addit!onalpagescontaining the following infonna~on.
Including middle initial andhighesLeamed degree

Co-Investigator:

S. Charles Schulz, M.D.

TelephoneNumber:

612.273.9 Pager or Cell Phone:

820

none

I Fax:

~-

Department Name:
Mailing Address: Department of Psychiatry 2 West Building/FUMC-Riverside 2450 Riverside Avenue Minnea~olis, Minnesota 55454

E-mail Address:

scs@umn.edu 02-11-2002

Oiginal Signature o! Co-Investigator

I Date

Co-Investigators responsible for, or working on this project should be listed below. Include any individual who will have responsibility for the consent process, direct data collection from subjects, or follow-up. If there are more than two Co-Investigators, please attac~ additional paRescontai~Lngthe following inf9rmation. Including middle initial and highestearneddegree

Co-Investigator:

John P. Vuchetich, M.D. Ph.d.

Telephone Number:

612.273.9
801
---

Pager or CellPhone:

I Fax:

Department Name:
Mailing Address:

I 612.273.7997 University 0

Fairview 0 Other:

Department of Psychiatry 2 West Building/FUMC-Riverside 2450 Riverside Avenue Minneacolis. Minnesota 55454

-Typed I

1. What is your research question? (Hypothesis).Pleasenote that the following questions must be answeredin lay languageor languageunderstood by a person unfamiliar with your area of research.Area-specific jargon should be avoided or explicitly explained.Do not say "seeprotocol".

Schizophrenia affects approximately 1% of the population and accounts for approximately 2.5% of the total health care expenditures in the United States. Schizophrenia is characterized by disorders in perception, content of thought and thought processes (hallucinations, delusions), and extensive withdrawal of individual's interest from other people and the outside world. People with schizophrenia are not able to distinguish between their delusions and realilty. They often have difficulty with cognition and memory. Onset typically occurs in the early to mid-20's for men and in the late-20's for women. The disease follows a chronic course with intermittent relapses, which are sometimes due to treatment interruption. It is estimated that medical treatment, social security payments, and lost wages due to schizophrenia amount to approximately $48 billion per year in the United States. Schizophrenia is one of the leading causes of hospitalization in the United States. Medical treatment of schizophrenia has been available since the early 1950's with the discovery of the first antipsychotic drugs (neuroleptics). These drugs represented a breakthrough in the treatment of schizophrenia, ameliorating the acute episodes and possibly preventing or decreasing the risk of occurrence of new episodes. However, these neuroleptics have considerable limitations (e.g., marginal control of positive symptoms, no prevention or control of negative symptoms, no effect on cognitive impairment) and are associated with several debilitating side effects {e.g., risk of extrapyramidal symptoms (EPS), elevation of serum prolactin, prolongation of QTc, and weight gain. More recently a class of medications known as the atypical antpsychotics have been developed. These medications have pharmacological properties such as 5HT2A/C and D2 antagonism. To date, these medications appear to have a lower incidence of serious side effects such as EPSand have been proven safe and efficacious through clinical trials. It has been proposed that atypical antipsychotic medication should be used

2. What research methods will you use? (How will you ask the question?)
Attach a protocol if applicable.

3.

What will the subjects be asked to do?

4.

Subject Population

a)

Location of Subjects During Research Data Collection

~ (Check all that apply)

D Schools - Elementary/Secondary
Community Clinic
I Prisons/Halfway

Specify:
houses

Fairview Southdale Hopital

-

Fairview RidgesHospital Other Fairview Facilities Other Hospitals

Specify:
Specify Specify

University Campus (nonclinical)

Other Special Institutions

d)

e)

-= -=

justification for unevengenderenrollment.

-

List criteria for inclusion and exclusion of subjects in this study

Inclusion Criteria:

1. Meets DSM IV criteria for schizophrenia disorder, schizophrenia, or schizophrenia disorder. 2. Has no previous history of significant pharmacological treatment with an antipsychoticmedication (greater than a total of 16 weeks of treatment). 3. Between 16 and 40 years of age. 4. Psychotic symptoms must have persisted at least one month and not more than five years (60 months). 5. Able to fully participate in the informed consent process, or have a legal guardian able to participate in the informed consent process. 6. Female patients of childbearing potential must be using a medically accepted means of contraception. 7. Score on at least one PANSSpsychosis items (Pi, P2, P3, PS, or P6) greater than and/or equal to and CGI Severity score greater than and/or equal to 4 (moderate) at point of maximum severity of illness to date. 1. Past history of any DSM-IV psychotic disorder with recovery. Recovery is defined as a period of at least three months with no active positive symptoms. 2. Patients with heavy co-morbid substance use, where the presenting psychotic symptoms are judged by the study physician as likely to be substance induced. 3. Female patients who are either pregnant or nursing. 4. Known history of mental retardation. 5. Non-English speaking ( mastery of English insufficient to participate in study evaluation procedures). 6. Serious, unstable medical illness. 7. Known allergy to any study medication. 8. At serious suicidal risk. 9. Participation in clinical trial of an investigational drug within 30 days of visit one.

Exclusion Criteria:

4.1)

-r==

Minority Group(s) and Non-EnglishSpeakers Specify: Pregnant Women Appendix C must be attached Fetus/FetalTissue Elderly Subjects(65 and over)
--

Provide rationale for using special populations

These groups are considered "vulnerable" or require special consideration by the federal regulatory agencies and by the IRB. Suggestion: Researchers should not select subjects on the basis of discriminatory criteria. Selection criteria that exclude one sex or racial group require a clear scientific rationale for the exclusion (See A endix C . Rationale: The goal of this study is to compare the effectiveness of, quetiapine, olanzapine, and resperidone for the treatment ofI ~ individuals suffering from a first episode of psychosis. This study will collect valuable information for physicians patients to use while planning treatment. and

5. Recruitment
5. a) Describe bow subjectswill be identified and recruited. Attach a copy of any and all recruitment materials to be usede.g. advertisements,bulletin board notices,e-mails, letters, or phonescripts.

5. b) Initial Contact
Describewho will make initial contact, and how it will be made. If subjects are chosenfrom records, indicate who gave approval for use of the records. If records are "private" medical or student records, provide the protocol, consentforms, letters, etc. for securing consentof the subjectsof the records. Written documentationfor the cooperation/permissionfrom the holder or custodian of the records should be attached. (Initial contact of subjects identified through records search must be made by the official holder of the record, i.e. primary physician, therapist, public schoolofficial.)

5. c) Is the study sponsoroffering anyincentive connectedwith subject

enrollment or completion of the study (i.e. finders fee, recruitment bonus, etc.) that will be paid directly to the researchstaff!

~ No 0 Yes.If yes describe.

5. d) Will subjects receiveinducementsbefore or rewards after the study?

0 No ~ Yes.If yes, please describe.

Pleasenote that this information must he included in the consent form, underthe heading "Compensation ", and not in tIle "Benefits" section.Also, payments for multiple visitsshould beproratetL

5. e) Will the subjectsbe charged for researchrelated procedures?If yes, explain charges,including estimatedamounts. This information must be specified in the consentdocument.

~ No DYes. Iryes,please describe.

6. Risks and Benefits

6. a) Does the Research Involve:

_;;k~ck all that applv) Any surgical process Igj Administration of drugs, chemical, or biological agents,or devices.Attach Appendix E

Administration of physical stimuli (beyond what is described on the Socialand Behavioral ~~~es form)
Major changes in diet or exercise

Use of private records (medical or educational records)

Possible invasion of privacy of subject or family Denrivation of Dhvsiolo!!ical reQuirements such as nutrition or sleep Manipulation of psychological or social variables such as sensory deprivation, social isolation, psychological stresses

~ Any probing for personalor sensitive informationin surveysor interviews

~ Use of a deceptivetechnique,e.g.,placebo,-louble-blind, etc. (suggestion:if deceptionis part of the experimental design,the protocol must include a debriefing procedure, which will be followed upon completionof the study or upon withdrawal of a subject. Attach a description of the debriefing protocol and any related materials.) Presentationof materials which subjects might consideroffensive,threatening, ~!"~~g!::a~in~ Other risks Specify:

6. b) Describethe precautions that will be taken to minimize the risk to the

subjects.

6. c) Why are the risks and inconveniences mentionedabove reasonable?

What is the expectedscientific yield from the project? Pleasejustify the risks in relation to the anticipated benefitsto the subjects,and in relation to the importance of the knowledge that may reasonablybe expectedto result from the research.

Benefits of Participation List any anticipated direct benefitsto participation in this researchproject. If none,state that fact here and in the consentform. The benefit of receiving treatment is not necessarily a benefit to participation in the researchproject. That distinction is central to the informed consentprocess.

7. Biological Samples
Blood drawing, marrow biopsy sampling, biopsy of other tissues, etc. If samplesof body fluids or tissuesare taken as part of this researchproject, state how much and how often the samplesare taken. The consentform must include lay term equivalentsfor the amounts, e.g.teaspoons etc. Please distinguish proceduresthat are diagnostic from proceduresthat are performed solely for research.

Patients will have their blood drawn at screening, month 3, month 6, and the final visit. Approximately two tablespoons of blood will be drawn. I Hair samples (small amounts) will be collected for Radioimmunoassay for the detection of substances of abuse. These samples will be collected at

.visits screen, 6 month, and end of study.

7. b) Will DNA be collected?

~ No 0 Yes. If yes, attach Appendix D.

7. c) Will tissue/bloodsamplesbe stored with identifiers?

~ No DYes. If yes,attachAppendixD.

8.

Care of subjects in case of an accident

Selectfrom one of the following compensation options listed below. This language mustbe included in the consentform. If a specialcontract to pay for researchrelated injuries exists, attach documentation for IRB record.

D Non-sponsor-funded compensation
In the eventthatthis research activity resultsin an injury, treatmentwill be available,including first aid, emergency treatment and follow-up careasneeded.Carefor suchinjuries will be billed in the ordinary manner, to you or your insurance company. If you think that you havesuffereda research relatedinjury let the studyphysiciansknow right away.

~ Sponsor fundedcompensation:
In the eventthatthis research activity resultsin an injury, treatmentwill be available,including fIrst aid, emergency treatment and follow-up careasneeded.Carefor suchinjuries will be billed in the ordinarymanner, to you or your insurance company. The sponsor of the studyhassome fundsavailableto pay for care for injuriesresulting directly from being in this study. If you think that you havesuffereda research relatedinjury and that you maybe eligible for reimbursement of somemedicalcarecosts,let the studyphysiciansknow right away.

D If the preferred injury compensation languageis unacceptableto the study sponsor,the following alternative languagemay be used:
Undersomecircumstances the sponsor of the study will pay for care for injuriesresultingdirectly from being in the study. If you want informationaboutthosecircumstances or if youthink you havesuffereda research relatedinjury let the studyphysiciansknow right away.

9. Confidentiality of Data
Describe provisions madeto maintain confidentiality of the data.

Where will the data be kept and for how long will it be kept?

The data will be retained for a minimum of fifteen

ears.

What security provisions will be used?Who will have access to the collected data? The study documentswill be kept secure. The investigator and study staff will have access to the data. Accesswill be provided for the sponsor's monitoring visits. Upon re uest, the Universi of Minnesota IRB and FDA will be allowed access. 9. d) Will data identifiying the subjectsbe made available to anyone other than the Principal Investigator, e.g.,FDA, study sponsor?

0 No ~ Yes. Please explainbelowand in the consent form.

Will the data be part of the medical chart or other permanent record?

~ No 0 Yes.Please explainbelowand in the consent form.

I
10. Expedited Review

After careful consideration of risks and review of the expedited review categories it has been determined that this research fits the precise requirements of category # -of the "Expedited Review" provision of 45 CFR 46, (see page vii.). The research could be considered of "minimal risk" to participants based on those i guidelines. (Note: Most research will not fit the categories for expedited review.) The decision to route the study via expedited review process will be determined upon review of the completed application by the IRB.

11. Informed Consent Process

11. a) Prepare and attach a consentform for IRB review.
Pleaseseethe sample consentform and follow it carefully. Do not submit sponsorprepared forms without editing the form to include IRB standard language.Seethe IRB Web site for the informed consenttutorial:

www.research.umn.edu/subiects.htm.

11. b) Describe what will be said to the subjects to introduce the research. Do not say "see consentform". Write the explanation in lay language.Hyou are using telephonesurveys,telephonesscripts are required.

11. c) What questions will be asked to assessthe Subjects' understanding? Pleaseanswer how you will assess subjects' understanding of the consent process.Questions requiring "yes/no" answersdo not do that very well. Pleaseask subjectsto explain the purpose of the study to you alongwith the risks and the henefits to themselves as participants. Their answersto these questionsshould allow you to determine if they understand the study and their part in it. If they do not understand, informed consenthas not been achieved evenif the subjectssigned the consentdocument.

The informed consent process for this study will include a formal procedllre

...

11. d)

In relation to the actual data gathering, when will consentbe discussed and documentationobtained? (e.g., pre-operatively, or severaldays before?)Be specific.

Written consent will be obtained prior to all study procedures.

1~"

Will the investigator(s)be securing all of the informed consent?

~ Yes D No. If no, please name the specific individuals who will obtain informed consentand include their job title and a brief description of your plans to train these individuals to obtain consentand answersubjects' questions.

I
IRB
D528 Mayo Memorial Building MMC 820 420 Delaware Street S.E. Minneapolis, MN 55455 See the meeting "Meeting Dates and Deadlines" page on the Research Subjects' Protection Programs' Web page: httR://www.research.umn.edu/subiects/index.html to find out the date of the meeting at which your application will be reviewed. If you have any questions, please call us at 612-626-5654.

You have reached the end of this form. Please make sure that you have responded to every question on this application (even if your response is "not applicable"). Submit 12 copies plus the original for Full Review, and 3 copies plus the original if you are requesting Expedited Review. Please send the application to: Research Subjects' Protection Programs

Research Staff are any personnel you wish to be included in correspondence relatedto this studye.g. studycoordinators.

Name: Department Name: Address:

Ruth M.Thomson University U Fairview Other:

)
I TeleDhone Number:

Ambulatory Research Center Department of Psychiatry 606 24th Avenue South Suite 602/Fairview Professional Building Minneapolis, Minnesota 55454

I 612.627.4823
I thomsO12@umn.edu

E-mail:

Check here if this is Fairview SystemResearch(not University faculty! staff! stu den t).

Peer Review

Is this research subject to review by another Committee? (If so complete the requested information)I It is the responsibility of the PI to secure the appropriate approval from these Committees and document that approval to _theIRB.

Committee
---

Date of Submission
Not Applicable

Institutional Animal Care and UseCommittee (IACUC) Cancer Protocol ReviewCommittee (CPRC) All University Radiation Protection Committee Conflict ManagementCommittee Nursing ResearchCommittee General Clinical ResearchCenter
Other IRB (name)
(i.e., if you are participating in a multicenter trial which requires the approval of other

Not Applicable
Not Applicable

Not Applicable
Not Applicable Not Applicable

Not Applicable

IRB's)

Other (specify)

Dean's Review/Conflict of Interest Review/Departmental Review

Pending

Jo./erability of Olanzapine, Quetiapine and Risperidone in the Treatment of First i

~-..

Design
Overview
is a randomized, double-blind, 24 centers psychotic disorder flexible dose, multicenter study of up to 400 patients of a non-affective disorder). (2.5-20 meeting DSM IV criteria for a first episode disorder,

(schizophrenia,

schizo affective

schizophreniform

Ranqomization

will be equally distributed (100-800 mg/day),

to one of three groups':'olanzapine and risperidone (0.5-4 mg/day).

mg/day) , quetiapine

3.2.

Rationale

for Study Design,

Doses

and Control

Groups

The study includes two principal phases, and a third optional continuation phase. Phase 1 is a screening phase, where patient eligibility is determined. Phase 2 is a 52-week double blind treatment phase. Drug will be initiated at the lowest possible dose in the dose range, and will be titrated according to a protocol, based on clinical response. During phase 2, study visits will occur at weekly intervals during the first 6 weeks of treatment, every two weeks from week 6 to week 12, and then monthly. All patients will receive a standardized 5 session psychosocial intervention that will provide education about psychotic disorders and the treatment of psychotic disorders, and address treatment adherence.

3.2.1.

Phase 1
and to collect baseline clinical information. Study

During phase 1 study subjects will participate in initial study evaluations to determine: phase 1 1 2 the study physician must. review t criteri of 3 weeks. To determine eligibility

results of all screening evaluations. III be discontinued at VO, and VO --

3.2.2.

Phase 2

Phase 2 is a 52-week double blind, randomized, treatment phase of the study. Subjects will have weekly visits from visit 1-6, biweekly visits for visits 6-12, and then monthly visits

thereafter.

3.2.3.

.Visit Intervals
and recommended visit intervals:

Below are the allowed

"

Phase 1: Screening Phase 2: VO-V5

1-21 days 5-9 days

2 days 7 days

--,II
~

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Storage and Inventory

Management

All product Will be monitored in a secure, limited access area at controlled room

temperature.
Quintiles will be responsible for'monitoringstudy distribution center below its re-order point, respective target level).
The Quintiles interactive

drug inventory at

and notifying the at the site falls site up to its

re-ordering

study drug rep.lacement

The Quintiles IVR system will expired 60 days prior to the expiratfon at the sites and prevent a subject Specific procedures for using Manual to be distributed at site
~

drug as

drug
date to

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

3.4.2. 3.4.2.1.

Doses and Treatment Regimens

Dosing

~ml~~!t~"l~~retionof the clinician with a minimal period between dose increases of 48 hours. Dose increases should be made based on cli~ical response and tolerability, and it is recommended that the length of the dosing intervals be increased if the subject experiences medication side effects. The recommended initial target dose is 2 study pills BID (e.g; BID of olanzapine, 200 BID quetiapine, or 1 mg BID of risperidone). 8 capsules a day administered in a BID schedule. recommended BID dosing must be maintained, and it is The maximum dose is

--

(but not required) that the larger dose be given in the evening when the split

doses are not equal. Dose decreases may be at any time and at any dosing increment at the discretion of the study clinician. Page 13

',,",,:;, ~,\.

Efficacy and Tolerabilityof Olanzapine, Quetiapine and Risperidone in the Treatment of.fir~tEpisode Psychosis: A Randomized Doui)le Blind 52 Week Comparison -', "".
-,

In many cases the subject will enter the study on antipsychotic treatment. Here, the clinician may chose to simultaneously decrease the prior antipsychotic and increase the study antipsychotic (e.g. cross-titrate the medications). Less frequently, the clinician may chose to The study abruptly stop the prior antipsychotic and initiate the study antipsychotic. transition from prior antipsychotic to the study antipsychotic. The following initial dosing schedule is recommended,but th~ clinician should individualize

physician should use his or her best clinical judgment when making decisions about

treatment in each ~ubiect based on toler~bilitv and clinic~1 response:

3'.4.2.2.

Discussion

of Dosing Design ~h~posing:trange1t.akes4trit'Q\thejfa'cco4Pf

The dosing range was chosen to allow clinicians maximal flexibility in dosing each antipsychotic medication in first episode patients. q~'c ~~~O:"{

usually respond &$; ,,::,~-Q,-,Gj;;"'.ed1~o~andwill be more likely to develop adverse

effects if the highest dose range of the antipsychotic medication is used. 1::/J,e~taai:b;g:~a5"S~

the..riskof

acut~ ~dverse~ffects,
-.,c..,~". ...;

and to max}mi.~~ init.i,al;t,oJ"~,(~bijitY,9f,e;ach",~eq).g,~ti9,n.i more rapid

titr~~~on.ra.te,couldinfl~te discontinuation rates due to acute adverse effects, and thus <potentially bias study results. The rationale for BID dosing relates to the fact that quetiapine needs to be administered BID, although risperidone and olanzapine may be administered once a day. In order to maintain the study blind, it will be necessary to administer all drugs twice daily. Other options (e.g. a mosaic design) would result in at least a partial break of the blind. The disadvantage of the BID dosing is that previous studies have shown that medication adherence is enhanced with <5ncedaily versus more frequent medication dosing. Thus, the potential advantage of a once a day drug versus twice a day drug on all-cause pharmacologic treatment discontinuation will not be assessed in this study: In summary, the advantage of different dosing schedules for the three drugs is substantially outweighed by the disadvantage posed by breaking the study blind. ,/'

Page 14