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The International Suicide Prevention Trial(InterSePT): Rationale and Design of a TrialComparing the Relative Ability of Clozapineand Olanzapine To Reduce Suicidal Behavior inSchizophrenia and Schizoaffective Patients

by Larry Mphs, Ravi Anand, M . Zahur Islam, Herbert Y. Meltzer,John M . Kane, Ranga Krishnan, Alan I . Qreen, Steven Potkin, Quy Chouinard,Jean'Pierre Lindenma yer, and Rob Kerwin

AbstractSuicidal behavior in patients with psychotic disordersrepresents a seriously undertreated life-threateningcondition. The International Suicide Prevention Trial(InterSePT) is the first large-scale, prospective studydesigned to evaluate the potential of antipsychoticmedications to reduce suicidal behaviors in patientswith schizophrenia or schizoaffective disorder who areknown to be at high risk for suicide. The unique chal-lenges to study design and the solutions identified forthe InterSePT study are described. These challengesincluded defining suicidal behavior in patients withpsychosis, endpoint selection, determination of ana-lytic strategy, and development of scales to assess sui-cidal behavior. Given the life-threatening nature ofsuicidal behavior, ethical considerations required thatthe design minimize suicide attempts and deaths.While the study focused primarily on treatment of sui-cide, opportunities were used to collect data in relatedareas of interest, including suicide risk factors, othere f f i c ac y m e a su r e s ( e .g . , Pos i t i ve an d N e g at i veS yn d r om e S c a l e , C ov i A n x i e ty S c a l e , C a l gar yDepression Scale), adverse events, pharmacoeconom-ics, and pharmacogenetics. Because of the complexityof the design issues, a steering committee, suicide mon-itoring board, and publication committee were estab-lished to assist with their management

Keyw ords: Suicide, suicidal behavior, schizophre-nia, schizoaffective disorder, study design, cloza pine,olanzapine.Schizophrenia Bulletin, 30(3):577-586, 2004.

Bleuler referred to the suicidal drive as "the most seriousof sch izophrenic sym ptoms" (Bleuler 1911, p . 488) .

Indeed, it is estimated that schizophrenia patients have a50 percent lifetime risk of attempting suicide. Annualdeath rates from suicide in this population have beenreported to be 0.4 percent to 0.8 percent, with a lifetimerisk of 10 perce nt (Nyman and Jonsson 1986; Axelssonand Lagerkvist-Briggs 1992; Meltzer and Fatemi 1995).Although suicidal behavior is well documented in psy-chotic patients, the magnitude of the problem is not gener-ally understood, risk factors are not well established orwidely recognized, and little information on the treatmentof suicidal patients is available. Consequently, a patient'ssuicide risk is seldom assessed in clinical practice. Inaddition, detection of suicide risk factors and preventionof suicide are particularly difficult because of the uniqueissues presented by patients with psychotic disorders.These patients are frequently beset with thought disorder,delusions, hallucinations, lack of insight, and negativesymptoms, all of which interfere with their ability to com-municate with their caregivers. Overall, suicidal behaviorin patients with schizophrenia and related disorders repre-sents a major public health problem that has not been ade-quately addressed by the medical community (Singh1998).

Existing data suggest that, for the most part, pharma-cotherapy for schizophrenia has not affected the rate ofsuicide among patients with psychotic disorders. Studieswith conventional antipsychotic medications have shownincreased (Beisser and Blanchette 1961; Hussar 1962),decreased (Johnson et al. 1983), or unchanged (Kline1959; Cohen et al. 1964; Planansky and Johnston 1971)rates of suicide in schizophrenia, and demonstrated that

Send reprint requests to Dr. L. Alphs, 765 Watershed Court, AnnArbor, MI 48105; e-mail: [email protected].

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the overall rate of suicide in schizophrenia was similarboth before and after the introduction of classical antipsy-chotics (Meltzer 1999; Palmer et al. 1999). In one study, a2 percent incidence of suicide was found among a cohortof 1,221 patients hospitalized for schizophrenia between1913 and 1940 with a subseque nt 11 years mean length offollow-up (Stephens et al 1999), suggesting a lower inci-dence of suicide in schizophrenia in an era withoutantipsychotics. Khan et al. (2001) analyzed data from aFood and Drug Administration (FDA) data base of 10,118patients who had participated in pivotal clinical trials witholanzapine, risperidone, and quetiapine. They comparedthe rates of suicide and suicide at tempts (in pat ientsexpected to be at reduced risk for suicide) during treat-ment with these drugs to those of patients randomized toplacebo and to those tak ing es tab l i shed (" typical" )antipsychotic drugs. Despite the large sample size, therates for suicide attempts were not statistically differentamong these three treatment groups. Overall, these dataare inconclusive, but suggest that neither typical nor atyp-ical antipsychotic medications reduce suicidal behaviorrelative to placebo.

Internationa l Suicide Prevention Trial(InterSePT) Rationale for ClozapineTreatment of Suicidal Behavior inSchizophreniaThe studies reviewed above do not include data on cloza-pine, however, several large, retrospective studies suggestthat clozapine may be effect ive for t reat ing suicidalbehavior in treatment-resistant schizophrenia patients whohave not been preselected for suicide risk (Meltzer andOkayli 1995; Walker et al. 1997; Reid et al. 1998; Munroet al. 1999; Sernyak et al. 2001). All but one of these stud-ies suggest that treatment with clozapine may signifi-cantly reduce suicide in this population. Only the study ofSernyak et al. failed to demonstrate the superiority ofclozapine over alternative therapies. However, althoughthis study included patients with a history of exposure toclozapine, it did not specify a minimal duration of treat-ment or whether patients were receiving active treatmentwith clozapine at the time of the index suicide attempt.AH of these studies leave open the question of whether apotential effect on suicidal behavior is limited to treat-ment - res i s tan t pat ien t s or appl ies more general ly topatients with schizophrenia or schizoaffective disorderwho are at risk for suicide.

Despite the evidence suggesting a clozapine effect onsuicidal behavior, few comparative studies have been con-ducted, and those that have been were not controlled forthe patient's risk of suicide, the dosage of drug treatment,

the use of concomitant medication, or the increased clini-cal contact required for blood monitoring during treat-ment with clozapine. The potential safety advantages ofmore recently introduced atypical antipsychotic agentshighlight the need for controlled comparative studies toevaluate whether clozapine differs from these drugs in themanagement of suicidal behavior.

The InterSePT study1 was conducted to address thelimitations of previous clinical trials and to establishwhether clozapine treatment is effective for reducing suici-dal behavior among schizophrenia and schizoaffectivepatients who were preselected to be at high risk for suicidebut were not otherwise treatment resistant. Because of thelack of prospective studies on which to model a protocolfor this clinically unstable population, the designers of theInterSePT study had to address numerous challenges sothat scientifically sound answers to the pressing questionsregarding treatment of suicidality in psychotic patientscould be found. Descriptions of the issues they faced andtheir solution in the InterSePT study follow.

Selection of Study Objective andEndpointsThe primary objective of the InterSePT study was toestablish whether clozapine provides therapeutic benefitfor reducing suicidal behavior in schizophrenia andschizoaffective patients at high risk for suicide. Becausemanipulative behaviors, expressed as suicide gestures, areal so seen in some subpopulat ions of sch izophreniapatients (e.g., those with borderline personality features),serious suicide attempts were distinguished from gesturesthat patients might have made to control their social envi-ronment. In this study, both the seriousness of suicidalintent and the lethality of means used to make that attemptwere evaluated by the patient's physician and by a blindedSuicide Monitoring Board (SMB).

In a psychotic population, a unique problem in deter-mining whether an event meets criteria for suicide arisesbecause the disease itself may cause patients to unknow-ingly put themselves at r isk of death. For example,patients may have command hallucinations that directthem to stop a moving train. If queried, such patientsmight deny that they are trying to kill themselves as theoncoming train, and certain death, approach. In studies ofsu ic ide, a pr ior i deci s ions mus t be made reg ard ingwhether this behavior represents a true suicide attempt.Because of the ambiguities in defining the nature and lim-its of suicidal behavior and the particular difficulty in

'The principal results of the InterSePT study have been publishedelsewhere (Meltzer et al. 2003).

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Design of the InterSePT Study Schizophrenia Bulletin, Vol. 30, No. 3, 2004

ascertaining patients' motivations after their death, suici-dal behaviors were defined in this study as behaviorscommitted by patients that put them at high risk of deathand resulted from (1) willful intent, (2) a response tointernal compulsions, or (3) disordered thinking.

Medical ethics requires that therapeutic t rials inpatients optimize both the clinical needs of the patient andthe scientific requirements of study conduct. In this studyof patients at high risk for suicide, ethical considerationsrequired that, at each contact made for collecting efficacyand safety data, every reasonable effort be made to pre-vent the patient from attempting suicide, even though thishas the potential to affect study outcome. Because of theneed to prevent these events , using suicide at tempts(including completed suicides) as the only measure ofoutcome in the InterSePT study was unacceptable. Inaddition, the duration and sample size for a prospectivestudy that only included suicide attempts or suicide deathsas endpoints would make it impracticable. As a conse-quence, interventions to prevent the immediate risk of sui-cide and clinical ratings indicating significant clinicalworsening in su ic idal behavior f rom basel ine wereincluded as primary endpoints.

The numerous potential endpoints that might havebeen chosen for this study required clear a priori specifi-cation for statistical analysis. After extensive consultationwith external clinical experts in psychiatry and statisticsand the Neuropharmacology Division of the FDA, twotypes of primary endpoints were designated. A type Ievent was defined as the occurrence of a significant sui-cide attempt or hospitalization because of imminent sui-cide risk (including increased level of survei l lance),which was confirmed by a blinded external group. A typeII event, determined by a blinded p sychiatrist, was definedas the occurrence of worsening of severity of suicidality,as indicated in a clinical global rating of suicidality of"much worse" or "very much worse" compared wi thbaseline. Because patients with potential type n eventswere not always observed by a blinded psychiatrist, crite-ria for a significant level of worsening from baseline werealso defined to have been met whenever a type I eventoccurred. The statistical management of these two diverseendpoints is described below (see "Statistical Analyses").

Patient SelectionThe InterSePT study was designed to include patientsfrom a diverse populat ion , enabling extrapolat ion ofresults to the larger group of patients with schizophreniaat risk for suicide. On the other hand, the population stud-ied had to be sufficiently enriched so that it could be c om-pleted in a limited time frame with feasible sample size.Minimal limitations were imposed to meet these criteria.

This study was limited to patients between the ages of 18and 65 with a DSM-IV (APA 1994) diagnosis of schizo-phrenia or schizoaffective disorder who were consideredto be at high risk of committ ing suicide. A high-riskpatient was any patient with a medical history of suicidalbehavior, including a previous serious suicide attempt orhospitalization to prevent a serious suicide attempt withinthe past 3 years. A serious suicide attempt was defined asa self-inflicted injury that put the patient at imminent riskof death. Alternatively, patients who demonstrated moder-ate to severe suicidal ideation with depressive symptomsor who had suffered from significant command hallucina-tions that put them at risk for self-harm at the time of ini-tial evaluation were eligible for enrollment in the study.Patients who met inclusion criteria were excluded fromparticipation if consent could not be obtained, if based onprior experience the patient was intolerant of clozapine orolanzapine, or if the patient would not be able to complywith the long-term followup required by the study.

Schizophrenia and schizoaffective patients from adiverse group of mult inat ional cl inical set t ings wereallowed to enter this study. They included patients from67 sites in 11 countries 2 who spoke at least eight lan-guages and were from many subcultures, socioeconomicgroups, and medical systems. The international characterof this study created an increased need for translations oftraining materials and pat ient record-related outcomedata.

Site SelectionBecause of the seriousness of the condition being exam-ined, the criteria for site selection received particularscrutiny. Above all, investigational sites had to includea principal investigator familiar with treating psychoticpatients at high risk for suicide. In addition, each sitehad to have sufficient support staff to be able to followthese patients during an extended period of observation.Staff at the site had to be familiar with the use of cloza-pine and be able to accommodate the stringent blood-monitoring requirements for using this drug. To ensureadequate pat ient enrol lment , the s i te was required tohave a flow of pat ients sufficient ly large to permitscreening of approximately 10 patients per month whowould meet study inclusion criteria. To ensure that fre-quent, regular contact (at least twice per month) withthe pat ient could be maintained, the si te had to belocated near the pat ient 's residence and have suffi-

2The 11 countries were Argentina, Canada, Chile, Croatia,Czechoslovakia, France, Hungary, Italy, South Africa, the UnitedKingdom, and the United States.

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ciently trained medical staff to manage these high-riskpatients. Finally, to comply with the requirements forblinded ratings, the site had to have a trained staff psy-chiatrist and usually one other skilled rater who couldserve as a blinded evaluator ("blinded psychiatrist") ofthe pat ient at regular intervals during the period ofobservat ion.Choice of Control DrugBecause standard ("typical") antipsychotic agents fre-quently produce extrapyramidal side effects, such as tar-dive dyskinesia and akathisia, which have been said toincrease suicidal behavior (Margolese et al. 2001), theiruse in a long-term trial was considered unacceptable.Furthermore, because the newer atypical ant ipsychoticagents have improved safety over older therapies, theywere considered more cl inical ly relevant as potent ialcomparators. From among these, olanzapine was chosenas the active comparator because of its broad availabilityat the time of study initiation, its pharmac ological similar-ities to clozapine, and its favorable tolerability profile. Inaddition, the literature suggests that it might have a favor-able impact on symptoms of suicidal behavior (Tran et al.1997). Treatme nt with olanzapine in this international trialwas co mplica ted by the fact that, at the time of study initi-ation, the optimal dosing recommendations varied amongthe countries involved in this trial. In the United States,the use of doses exceeding 10 mg was not recommended,al though cl in ical pract ice sugges ted that in cer ta inpatients the use of higher doses might be clinically indi-cated. Given the life-threatening condition being studied,permission was sought and gained from the U.S. regula-tory authorities to allow the use of doses higher than 10mg, based on the clinical assessment of the treating psy-chiatrist.

Visit FrequencyA requirement for treatment with clozapine is frequenthematological laboratory testing to ensure that patients donot develop agranulocytosis.3 Despite general agreementon the need for monitoring, the frequency varies by coun-try. For this study, it was decided that the frequency ofsafety monitoring would reflect the most conservativerequirements held by any of the participating countries. Inaddition, all local safety requirements for clozapine usewere respected. Thus, patients were to have weekly visits

3 Agra nulo cytos is has been reported in 1 percent to 2 percent ofpatients treated with clozapine (Kane et al. 1989).

for the first 6 months and then biweekly visits for theremainder of the study.Some clinicians have speculated that the high fre-quency of contact with medical personnel that occurs as aconsequence of clozapine blood-monitoring programsmight explain reports of suicide reduction with this treat-

ment. Failure to control for this contact has been consid-ered a significant design flaw in previous studies. To elim-inate the possible confounding effects of increasedclinical contact, visit frequency and makeup in this studywere identical for the clozapine and olanzapine treatmentgroups. All pat ients , no matter what their t reatmentassignment, were required to have frequent study-relatedvisits. Clinical contact, including assessment for suicidal-ity, was similar at each of these visits for both groups.Clozapine-treated patients had blood monitoring at eachof these visits, and vital signs were assessed less fre-quently. Olanzapine-treated patients were not required tohave such frequent blood monitoring, as it was clinicallyunnecessary. Instead, their vital signs were recorded dur-ing visits corresponding to the blood-monitoring visits forclozapine-treated patients.

BlindingThe clinical side effect profiles of olanzapine and cloza-pine and the increased frequency of blood draws forclozapine-treated patients made it implausible that thetreatment blind could be maintained for either the subjector the treating physician over a 2-year period of observa-tion. Another concern was that, because participating sub-jects were at high risk for suicide, they required particu-larly close clinical monitoring that was comprehensiveand flexible. To optimally provide this, knowledge of thepatient's treatment regimen by the primary treating physi-cian was considered essential. These constraints resultedin a decision to use an open-label study design.

To meet requirements for a scientifically valid andwell-controlled trial that would provide convincing evi-dence of a differential treatment response between cloza-pine and olanzapine for suicidal behavior, determinationof primary endpoints had to be completed in a blindedfashion. Therefore, blinding was implemented at the sitelevel and the study level. In addition, throughout thestudy, all endpoint and safety data reviewed by the studysponsor 's cl inical and administrat ive personnel wereblinded.At the site level, a rater who was blinded to thepatient's treatment assignment was needed to determinewhether the patient demonstrated significant worsening ofsuicidal behavior from baseline. It was recommended thatthe number of raters per center be large enough to coverperiods of illness and vacation but small enough and with

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minimal turnover to reduce interrater variability. In gen-eral, having two to three raters per center was recom-mended. At each study visit, raters documented whetherthey remained blinded to the patient's treatment co ndition.If they became unblinded, their ratings after the point ofunblinding were disqualified and a new, blinded rater wasidentified. Study m onitors systematically checked c ompli-ance with this requirement.

In addition to blinded site raters, a centralized groupof expert raters independent of the site and study spon-sora Suicide Monitoring Board (SMB)was created tomake blinded decisions about whether a potential end-point met criteria for suicidal behavior and whether it rep-resented an imminent risk of suicide. They also assessedthe seriousness and lethality of the attempt. This single,centralized group was identified because such decisionsneeded to be made consistently across all centers. TheSMB was composed of three experts not otherwise con-nected to the s tudy: Ra nga Kri sh nan f rom D ukeUniversi ty; Hannale Heila from the National PublicHeal th Ins t i tu te in Hels inki , F in land; and IsaacSakinofsky from the University of Toronto. They wereselected from different parts of the world on the basis oftheir expertise in suicidal behavior and their knowledge ofboth schizophrenia and the experimental design of suicidestudies. Each had extensive experience in working withsuicidal patients. The chair of the SM B, Dr. Krishnan, hadexperience in the design and operation of large multicen-ter clinical studies. This team remained constant for theduration of the study.At the onset of the study, this team developed the

specific procedures for what and how data would bereviewed and set guidelines for how cases would be eval-uated. Blinding of the SMB was monitored by Dr. KevinCox from Ingenix Pharmaceutical Services. He wasresponsible for ensuring that all data received by the SMBwere blinded. The SMB members were forbidden to havecontact related to the trial with sites and other participantsin this study. The institutions for which the SMB mem-bers worked were not included as participant sites. Anyquestions SMB members had about the study were com-municated to Dr. Cox, who then communicated with thestudy sites.All information received by the SMB underwent anextensive series of reviews to ensure that it was completeand blinded. This multistep process is illustrated in figure1. As a first step in data blinding, the principal investiga-tors at each si te reviewed potent ial endpoint cases,removed information that might unblind the reviewer tothe patient's treatment condition, and sent documents thatwould be reviewed by blinded raters to a central medicalmonitor. In addition, to ensure that all relevant potentialen d p o i n t s were co l l ec t ed , m o n i t o r s r ev i ewed each

patient's clinical records, including all reported adverseevents and serious adverse events, for any incident thatmight have rep resented an overt or covert self-injuriousact that met criteria for a potential endpoint. Such cases,not already identified by the site, were flagged for review.Only cases of self-evidently nonserious self-inflictedinjury were excluded from additional followup. Extensivedata on all cases of potential suicide, suicide attempt, orhospitalization for imminent risk of suicide were trans-lated when necessary and sent to a medical reviewer toensure that they had been adequately blinded. This pack-age of material included background information; infor-mation on the index event; any associated hospitalizationor rescue intervention; all relevant, obtainable medicalrecords pertaining to the event; recent ratings on depres-sion and suicidal behavior that had been completed by theblinded psychiatrist; and records on drug compliance. Dr.Cox reviewed this material to make certain that any men-tion of the patient's treatment and any signs or symptomsthat might reveal the patient's treatment (e.g., drooling,regularly reported white blood cel l counts , excessivedrowsiness, hypotension) were eliminated from the casedescriptions. Once this review was complete, the informa-tion was submitted to the SMB members who individuallyreviewed the cases to determine whether the incidents metcriteria for an endpoint. If there was disagreement amongthem, they discussed the findings on a conference call anddeveloped a consensus rating. This included classificationof each self-damaging act as either a suicidal gesture or asuicide attempt.

To establish concurrent reliability for the SMB deci-sions, material on each potential endpoint was forwardedin parallel to the on-site blinded psychiatrist. This psychi-atrist reviewed this material and made an independentdetermination of whether criteria for an endpoint weremet.

Clinical AssessmentsTo provide secondary data that would supplement thecharacterization of the patients and the effects of treatingthem with clozapine or olanzapine, ancillary data werecollected. These included data to assess suicidal ideation,depression, anxiety, psychosis, extrapyramidal symptoms,overall functioning, safety, and health economics. In addi-tion, information was collected on cognition and insightfor subsets of patients who participated in this trial.

Because no prior prospective studies had examinedt reatment ef fect s on su ic idal behavior in psychot icpatients, little work had been done to develop scales toassess symptoms of suicidality in patients with psychoticdisorders. As a consequence, several new scales were cre-ated in preparation for this study. The Beck Suicide Scale

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Figure 1. Primary Endpoint Data Flow for Type I Events 1

Information on PotentialSuicide EventsPEP

PrincipalInvestigator

IngenixMedical Monitor

PEP

Database

LegendSMB = Suicide Monitoring Board

PEP = Potential Endpoint PackageSEF = Suicide Event Form -SMB

1 Blinded psychiatrist has no role in determining primary type I events.

(Beck et al. 1979) was used as a model for the InterSePTScale for Suicidal Thinking (ISST), which was used asone measure of suicidality in this study. This scale wasdeveloped for use with a semistructured interview tostandardize the collection of information on suicidalityused to rate this scale and a global scale of suicidality(see next paragraph). This s tandardizat ion was espe-cially important for a large multicultural study in whichindividual approaches to rating suicidality might other-wise vary widely across centers , countries , and lan-guages. The long duration of the trial also resulted inchanges in raters and increased the need for standard-ization of the rating process so that ratings would bevalid over time. Furthermore, individual items on thesuicide scale had to be adapted to be relevant for psy-chotic patients and ratings had to be anchored to reflectthe needs of a pharmacological trial.

A global assessment of suicidality was created forthis s tudy to provide an index to assess an expert 'sassessment of suicidal behavior that would help confirmthe validity of the ISST. This global scale (the ClinicalGlobal Impression of Suicidality) included two assess-ments of the patient 's suicidality. One rating assessed(on a 5-point scale) the most severe level of suicidalityexperienced by the patient during the previous 7 days.The second rat ing assessed (on a 7-point scale) howmuch the patient 's suicidality had changed from base-l i n e . Development of these scales i s descr ibed inLindenmayer et al. (2003).

Trial DurationNo data relevant to the evaluation of a schizophrenic pop-ulation at high risk for suicide were identified in the pub-lished literature. Consequently, it was difficult to identifya basis for determining the appropriate duration of treat-ment for this study. Based on a review of the availableepidemiologic data and treatment outcomes of suicidalityin patients with schizophrenia (Rennie 1939; Winokur andTsuang 1975; Cohen et al. 1990), a 2-year duration ofclinical observation was selected as short enough to makethe study logistically and economically feasible but longenough to capture a sufficient number of endpoints toidentify cl inical ly meaningful t reatment differencesbetween clozapine and olanzapine.

Sample SizeThe sample size was calculated based on the rate ofoccurre nce of type 1 events. It was hypothesized that thepercentages of event-free subjects during the 2-yeartreatment phase in the clozapine and olanzapine treat-ment groups would be 55 percent and 45 percent ,respectively. Using a two-sided log-rank test with a sig-nificance level of 0.05 and a statistical power of 80 per-cent, it was determined that, if the treatment hypothesisheld, a total of 381 patients with at least one type 1 event(or a total of 762 subjects) would be needed to differen-

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t i a t e t h e t wo t r ea t m en t s (F reed m an 1 9 8 2 ) . Wi t hallowance for an estimated overall dropout rate of 15percent, it was concluded that approximately 900 sub-jects (450 subjects in each group) would need to be ran-domized.

Patient Management and RescueInterventionsA forem ost co nce rn of this study was patient safety,including reduction of suicide attempts and preventionof deaths from suicide. Every effort was made to sup-port this goal. To this end, patients in both treatmentgroups were seen by an unblinded health care profes-sional weekly for the first 26 weeks and biweekly there-after. During this visit, the health care professional wasrequired to ask at least two questions to assess eachpatient's level of suicidal ideation. If a patient's suicidalideation, depression, or psychosis worsened during thecourse of the s tudy , the t reat ing psychiat r i s t wasdirected by the protocol to take whatever clinical mea-sures were necessary to reduce these symptoms and pre-vent an event from occurring. Concomitant medications(all types, including adding other antipsychotics), elec-troconvulsive therapy, hospital izat ion, psychotherapy,and all other appropriate means were allowed. It wasrecommended that all possible therapeutic interventionsbe implemented before a patient 's participation in thetrial was terminated. In support of this approach, treat-ment algori thms for pat ients with worsening of psy-chosis or suicidal behavior were provided to treatingclinicians.

DropoutsGiven previo us exper ience in t reatm ent s tudies ofpatients with schizophrenia (Tran et al. 1997), it wasexpected that a large number of patients would drop outfrom the study and potentially be lost to followup beforecompleting 2 years of observation. A large dropout ratewould have biased the estimated treatment effect, if thedropouts were nonrandom. In particular, if the rate andtime to dropout were related to the treatment assign-ments, the results would be difficult to interpret. To getas complete a picture of patient response as possible,every effort was made to follow patients and assess clin-ical outcome for the entire 2-year period of involvement.To facilitate this, patients were allowed to reenter thestudy, if they desired. In addition, a limited amount ofinformation assessing primary cl inical response wasobtained in as many dropouts as could be found and whowould agree to provide it.

Statistical AnalysesPrimary efficacy analyses for this study were performedon the intent-to-treat population, which included all ran-domized patients, whether or not the patients received anytreatment and whether or not the treatment designated inthe protocol was taken. Safety analyses were completedon a "safety population," which consisted of all random-ized patients who took at least one dose of study medica-tion.

The primary efficacy variables were defined as thetime (in days, after randomization) to the first occurrenceof any of the primary outcome events described above(see "Select ion of Study Object ive and Endpoints").Because (1) patients could experience multiple events, (2)the two types of events were not identical, and (3) thetime to an event could be censored for patients with noevents, the primary statistical analysis of these variableswas based on the approach of Wei, Lin, and Weissfeld(Wei et al. 1989), commonly known as the WLW method.This analysis is a semiparametric method used to analyzemultivariate failure time data. This method models themarginal distribution with a Cox proportional hazardsmodel . For the primary analysis , pooled country wasincluded as the strata variable and treatment group as theonly covariate. Countries with a small number of patients(


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Calgary Depression Scale (CDS; Addington et al. 1994),diagnosis, substance (drug or alcohol) abuse, total scoreof the Extrapyramidal Symptoms Rating Scale (i tems1-55; Chouinard et al. 1980), total score of the positivecomponents of Lindenmayer's five-factor model of schiz-ophrenia (Lindenmayer et al. 1994), hopelessness score(item 2 of the CDS), and total score of the Covi AnxietyScale (Covi et al. 1981).

Supervising CommitteesTwo supervisory committees in addition to the SMB wereformed to facilitate the activities of the InterSePT study.An international group of expert advisors was broughttogether as a steering committee to provide oversight forthe cl inical and scient ific aspects of the study. TheInterSePT Steering Committee consisted of five indepen-dent experts on schizophrenia (none of whom participatedas investigators in the trial), a m edical representative fromthe study sponsor, and an independent statistician. Thiscommittee was created to address key issues that aroseduring the study and to advise on and approve all amend-ments to trial design and study conduct during the study.They were also responsible for reviewing site perform-ance, reviewing interim analysis reports, and, if necessary,recommending study termination for reasons of safety. Inaddition, they approved the conventions developed by theSMB for assessing endpoints related to suicide attemptsand hospitalizations to prevent suicide.

Because of the unique and clinically important natureof the data being collected in this trial, a publication com-mittee was created at the time the trial was initiated. Thisgroup, consisting of leaders from the study sponsor andleading academic experts in schizophrenia and suicidalityfrom across the world, was responsible for identifyingpotential publications that might be generated from thistrial and ensuring that they were completed in a scientifi-cally consistent and efficient process so that they wouldbe maximally informative to the medical community. Adetailed charter for this publication committee was devel-oped from the outset to maximize the publication commit-tee's focus and effectiveness.

Logist ical M anagem entA c l i n i ca l r e s ea rch o rg an i z a t i o n (C R O ) ( In g en i xPharmaceutical Services) was employed to manage thelogistical aspects of the InterSePT study. Its role wasespecially important because of the complexities of theendpoint evaluation process. All operational activitieswere performed by the CRO from the outset of the study.In addition, this group played a crucial role in maintaining

the study blind. The CRO was responsible for communi-cation among sites, blinded raters, the steering com mittee,and the SMB and for maintaining a "firewall" that wouldprevent unblinding of blinded raters and the study spon-sor. The data base was maintained by the CRO and trans-ferred to the sponsor only after all data were cleaned,coded, and locked for the final analyses.

ConclusionsSuicide is the major cause of death in schizophrenia andaccounts for approximately 10 percent of deaths am ongpsychiatric patients (Nyman and Jonsson 1986; Axelssonand Lagerkvist-Briggs 1992; Meltzer and Fatemi 1995). Itis a human tragedy not only for its victims but also for theestimated six or seven immediate survivors of each victim(Singh 1998). The InterSePT study was conducted in aneffort to lessen this tragedy.

This is the first study of its kind to prospectivelyevaluate effects of clozapine or any other antipsychoticmedication on suicidal behavior. A primary challenge wasto detect differences in long-term outcome among thetreatment groups on a number of endpoint measures (e.g.,suicide attempts), while simultaneously using all meansnecessary to prevent this unacceptable clinical o utcome.Because of its many challenges, successful comple-tion of the InterSePT study required a unique partnershipamong academicians, regulatory authorities, health careproviders, patients and their caregivers, and the organiza-tion sponsoring this trial. This need for collaboration wasidentified well before the study was initiated and contin-ued after its conclusion. Overall, this close interactionamong participants from industry, academicians, and clin-icians represents a model for conduct of complex clinicalstudies.The study design resolved a number of complexissues and methodological challenges, and data resultingfrom it promise to significantly increase our knowledge ofsuicidal behavior in schizophrenia. Even so, it is likely togenerate more questions than it answers in this highlycomplex field and will hopefully spark interest in con-ducting similar trials that will identify other effective ther-apies for suicidal behavior.

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AcknowledgmentsAppreciation is expressed for the work of John Messina,Richard Hartman, Mojtaba Noursalehi, and Frederick Youngfor their support and thoughtful contributions to the design ofthis study and its write-up and also to the InterSePT StudyGroup for their participation in the conduct of this work.

The AuthorsLarry Alphs, M.D., Ph D ., is Executive Director, Pfizer GlobalResearch and Development, Ann Arbor, MI. Ravi Anand,M.D., is Consultant, Basle, Switzerland. M. Zahur Islam,Ph.D., is Director, Novartis P harmaceuticals, East Hanover, NJ.Herbert Y. Meltzer, M.D., is Professor, Vanderbilt University,Nashville, TN. John M. Kane, M.D., is Director, PsychiatricResearch, Long Island Jewish-Hillside Medical Center, GlenOaks, NY. Ranga Krishnan, M.D., is Professor andChairman,Department ofPsychiatry, Du ke University, D urham, NC . AlanI. Green, M.D., is Professor and Chairman, Department ofPsychiatry, Dartmouth University, Hanover, NH. StevenPotkin, M.D., is Professor, Department of Psychiatry,University of California, Irvine, CA. Guy Chouinard, M.D.,M.Sc., FRCR is at McG ill University, Montreal, Canada. Jean-Pierre lindenmay er, MD., is Clinical Professor of Psychiatry,Manhattan Psychiatric Center-Nathan Kline Institute forPsychiatric R esearch, Wards Island, NY. Rob Kerwin, M.D., isat K ings College, Institute of Psychiatry, London, England.

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