Double-Blind Comparison of Olanzapine versus Clozapine in Schizophrenic Patients Clinically Eligible for Treatment with Clozapine

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1 Double-Blind Comparison of Olanzapine versus Clozapine in Schizophrenic Patients Clinically Eligible for Treatment with Clozapine Gary D. Tollefson, Martin A. Birkett, Gerilyn M. Kiesler, Andrew J. Wood, and The Lilly Resistant Schizophrenia Study Group Background: The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptic drugs is a major challenge. Clozapine has been one treatment option; however, it is not universally effective and is limited in its use by safety concerns. With the introduction of newer agents, their performance relative to clozapine is of great clinical interest. Methods: The primary objective of this study was to evaluate the efficacy and safety of olanzapine versus clozapine among treatment resistant DSM-IV schizophrenic patients. The study was primarily designed to demonstrate the noninferiority of olanzapine compared to clozapine after 18 weeks of double-blind treatment. Conclusions were based on the one-sided lower 95% confidence limit about the treatment effect observed from the primary efficacy variable (Positive and Negative Syndrome Scale [PANSS] Total). Results: Mean changes from baseline to end point in PANSS Total score, using a last observation carried forward technique, showed that both agents were comparably effective in neuroleptic resistant patients, i.e., demonstrated the noninferiority of olanzapine when compared to clozapine. Overall, significantly fewer olanzapine-treated patients (4%) discontinued for an adverse event than their clozapine-treated (14%) counterparts (p.022). Among spontaneously reported adverse events, increased salivation, constipation, dizziness, and nausea were reported significantly more often among clozapine-treated patients, whereas only dry mouth was reported more often among olanzapine-treated patients. Conclusions: Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (GDT, GMK), Eli Lilly and Company Limited, Lilly Research Centre, Windlesham, United Kingdom (MAB), and Lilly Development Centre, Mont- Saint Guibert, Belgium (AJW). Address reprint requests to Gary D. Tollefson, M.D., Ph.D., Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 2033, Indianapolis IN Received September 8, 1999; revised March 13, 2000; revised August 1, 2000; accepted August 4, schizophrenic patients clinically eligible for treatment with clozapine. Biol Psychiatry 2001 Society of Biological Psychiatry Key Words: Olanzapine, clozapine, treatment resistant, schizophrenia, clinical trial Introduction The treatment of schizophrenic patients who fail to respond to or tolerate adequate trials of neuroleptics is a major challenge (Ciompi 1980; Kane 1996). It has been repeatedly demonstrated that many schizophrenic patients either do not respond or only partially respond to conventional dopamine-d 2 antagonist antipsychotic agents; estimates vary between 40% and 80%. Even among patients who respond in terms of core psychotic symptoms, other disease manifestations, including negative, affective, and anxious symptoms, may go unimproved. These features contribute significantly to individual patient disability. Furthermore, a number of adverse events characterize the currently available conventional antipsychotic agents (Kane 1989). The severity of these adverse events in a considerable number of schizophrenic patients contributes to poor compliance (Corrigan et al 1990; Weiden et al 1986). These adverse events include extrapyramidal syndromes (EPS; Chouinard et al 1988), such as drug-induced parkinsonism, acute dystonic reactions, akathisia, tardive dyskinesia, and tardive dystonia. Other reasons for drug intolerance include sexual dysfunction, cognitive dulling, seizure, or galactorrhea and gynecomastia attributable to hyperprolactinemia. Novel antipsychotic compounds that minimize such adverse events and/or improve the breadth and depth of clinical response offer the chance to improve overall patient outcomes (Kinon and Lieberman 1996; Meltzer 1991). Although such benefits have been demonstrated in standard subject populations, a greater challenge is pre Society of Biological Psychiatry /01/$20.00 PII S (00)01026-X

2 Olanzapine vs. Clozapine in Schizophrenia BIOL PSYCHIATRY 53 sented by an intolerant or resistant schizophrenic patient group. Subjects who have failed to benefit with conventional antipsychotic drugs constitute a particular and significant public health concern, by virtue of their significant morbidity, mortality, and societal cost (Malhotra et al 1996). Clozapine, an atypical antipsychotic drug, with pharmacologic features that distinguishes it from conventional neuroleptic agents, represents one such novel alternative (Carlsson 1988; Coward 1992; Meltzer 1989,1992). In several multicenter clinical trials clozapine has been shown to be effective in the treatment of DSM-III schizophrenic patients who have failed to respond to a variety of conventional neuroleptics (Conley et al 1988; Hirsch and Puri 1993; Kane et al 1988). These treatment benefits may include improvement in positive and/or negative symptoms in schizophrenic patients (Naber and Hippius 1990). Resultingly, clozapine has been approved specifically for patients with schizophrenia who have proved intolerant of and/or nonresponsive to conventional neuroleptic agents. Olanzapine represents another novel alternative. Although exhibiting a similar in vitro profile to clozapine, unique differences are evident (Bymaster et al 1996). Clinical studies have shown that olanzapine is effective in the control of psychotic symptomatology, including both positive and negative symptoms among both acute and chronic schizophrenic populations. Moreover, the rate of early discontinuations attributable to adverse events is significantly less than that seen with haloperidol (Beasley et al 1996; Tollefson and Sanger 1997). Given these apparent safety advantages, olanzapine may also be well suited for the treatment of treatment-resistant schizophrenic patients (Miller et al 1994). This study was designed to evaluate the efficacy and safety of olanzapine compared with clozapine in schizophrenic patients who have been classified as having treatment-resistant psychopathology eligible for treatment with clozapine. Methods and Materials Study Design The study was designed a priori as a noninferiority study, or therapeutic equivalence study (Garbe et al 1993; Rohmel 1998). The design is becoming more commonly used in studies where the comparator is an established reference drug in clinical practice. Trials to demonstrate the superiority of one treatment to another are common, but in the case of an active controlled trial the demonstration of superiority for the investigational drug is considered unlikely or would require too many patients to be practically and financially feasible. Failure to demonstrate a statistical difference in favor of the investigational drug cannot, of course, be used as proof of equivalence to the active control, hence the study must be designed with the specific hypothesis of noninferiority in mind. Interpretation of data from noninferiority trials is made on the basis of confidence intervals. In such trials, the upper limit of the confidence interval (in this case how much better the investigational drug might be compared to the active control) is of little interest, because we only want to try and reject the null hypothesis that the investigational drug has less efficacy than the control, for which we utilize the lower limit of the confidence interval. Once rejected we can conclude that the investigational drug is not inferior to the active control, meaning that we have not ruled out the potential superiority compared to the active control, a question that cannot be answered in the present study, because it was not designed for this purpose. The conclusions are based on interpretation of the one-sided lower 95% confidence limit about the treatment effect observed from the primary efficacy variable, and whether this confidence limit lies in the correct half space compared to (all values larger than ), which marks the limit for differences that are considered clinically acceptable. was selected a priori to avoid accusations of setting the clinically acceptable limit in a biased manner based on observed data; however, there are no generally accepted guidelines on how this clinically acceptable limit should be chosen. The study was conducted by 41 investigators in 14 countries (Belgium, Denmark, Finland, France, Germany, Italy, Norway, Portugal, South Africa, Spain, Sweden, Switzerland, Great Britain, and Ireland). All investigators and raters were English speaking. The study protocol was approved by local ethical review boards, and a signed informed consent was obtained from all eligible patients after the procedures and possible side effects were explained. The study consisted of three periods: 1) a washout period from previous antipsychotic drugs (2 9 days for oral antipsychotic drugs; at least one injection cycle for depot antipsychotics); 2) an 18-week double-blind therapy period in which patients were randomly allocated in a 1:1 ratio to treatment with olanzapine mg/day or clozapine mg/day; and 3) an optional open-label extension period of up to 3 years or until olanzapine became available in the relevant country (for olanzapine-treated patients only). To ensure uninterrupted availability of the appropriate treatment at the end of the double-blind study period, patients were unblinded after 18 weeks of therapy. Randomized patients started olanzapine at 15 mg/day once daily, or clozapine at a fixed dose escalation from 25 mg to 200 mg/day during the first 8 days of therapy. Flexible dosing, across a range of mg daily for olanzapine and mg daily for clozapine was permitted after the first 2 weeks of doubleblind treatment. With either drug, blinded titration was permitted to optimize an individual patient s outcome. Investigators had the opportunity to increase or decrease the dosage by either 2.5 or 5 mg of olanzapine, or by 50 or 100 mg of clozapine per visit interval (as per manufacturer s instructions). Concomitant psychotropic medications were not allowed during the study with the exception of a benzodiazepine (up to 40 mg/day diazepam equivalent or 8 mg lorazepam equivalent) for agitation, chloral hydrate for insomnia, and biperiden or benztropine mesylate (up to 4 mg/day) for treatment-emergent EPS. Prophylactic use of anticholinergic medications was prohibited.

3 54 BIOL PSYCHIATRY G.D. Tollefson et al Sample Size The study was designed to be able to evaluate the noninferiority of olanzapine versus clozapine based on the one-sided lower 95% confidence limit of the difference between treatments in change in Positive and Negative Syndrome Scale (PANSS) Total scores. A sample size of 220 patients (110 per treatment group) was planned, assuming an expected treatment effect of 4 units (in favor of olanzapine), with a common SD of 22 units, 85% power, and a one-sided significance level of.05. The clinically acceptable limit ( ) of 4 units for the treatment effect was selected and denoted a priori in the protocol for the basis of declaring the noninferiority of olanzapine compared to clozapine. The lower limit was chosen to be 25% of what we estimated the overall treatment benefit (i.e., change from baseline to end point in PANSS Total score) would be; in this case we assumed 16 units. Patient Population Patients were men or women between the ages of 18 and 70 years who met with a clinical diagnosis of DSM-IV criteria for schizophrenia and who had a minimum score on the Brief Psychiatric Rating Scale (BPRS 1 7 ), extracted from the PANSS (Kay et al 1987), of at least 45 and a score of 4 or more on at least 2 items of the PANSS Positive symptom subscale (items 1 7). Patients who had previously been treated with olanzapine or who were olanzapine or clozapine nonresponders were specifically excluded from this study. All study participants were required to have a documented history that they were clinically resistant to previous antipsychotic treatments. Resistance was defined as a lack of satisfactory clinical response to at least 2 previous oral neuroleptic treatments, each of a different chemical class, given for a duration of at least 6 weeks at an appropriate daily dosage equivalent to at least 500 mg chlorpromazine, or to the maximum daily dosage when intolerable side effects had been documented. Patients known to be intolerant to either clozapine or olanzapine were not included. Patients could begin the study as inpatients or outpatients, and changes in hospitalization status during the protocol were permitted. All patients who commenced the study as inpatients were returned to outpatient status within 2 weeks of randomization to double-blind treatment. Pregnant or lactating women, or patients with serious medical illnesses in which pharmacotherapy posed a substantial clinical risk or confounded diagnosis, were excluded. Assessments Clinical assessments were carried out at the screening visit and again at the baseline assessment. Postrandomization assessments were conducted weekly up to 18 weeks, throughout the study for safety. For efficacy, assessments were performed weekly for the first month, every 2 weeks for the next 6 weeks and finally every 4 weeks for the remainder of the study. At the screening visit a standard history, physical examination, and laboratory profile were obtained. Hematology tests were performed at baseline as well as weekly during the 18-week treatment period. Serum prolactin was measured at baseline and at end point. The efficacy measures included the PANSS Total score (primary efficacy measure) and its subscales (positive and negative); the 18-item BPRS 1 7 total extracted from the PANSS and the Clinical Global Impression Severity of Illness Scale (CGI-Severity). Adverse events were detected by clinical evaluation and spontaneous report at each visit and mapped, classified, and recorded using a system based on the U.S. Food and Drug Administration Coding Symbols and Thesaurus for Adverse Reaction Terms (COSTART; U.S. Food and Drug Administration 1990). In addition, adverse events were solicited by the investigator using the 40-item Association for Methodology and Documentation in Psychiatry (AMDP-5) adverse event questionnaire (Association for Methodology and Documentation in Psychiatry [Arbeltsgemeinschaft fur methodik und dokumentation in der psychiatrie] 1981; Guy and Ban 1982). Extrapyramidal symptoms, akathisia, and dyskinesia were further assessed with the Simpson Angus Scale (Simpson and Angus 1970), the Barnes Akathisia Scale (Barnes 1989), and the Abnormal Involuntary Movement Scale (AIMS; Guy 1976). The modal daily dose was defined as the most frequently administered daily dosage of study drug for each individual patient during the 18-week double-blind therapy period; the maximum daily dose was defined as the highest dose given to a patient even if only for one day. The average daily dose is calculated for each patient by deriving the cumulative dosage received during the study divided by the number of days of therapy. All investigators attended a formal and standardized start-up meeting, country by country, during which they were trained on how to complete the different scales. No formal inter-rater reliability was performed. Statistical Methods The primary intent of this study was to evaluate the effectiveness and safety of olanzapine versus clozapine during double-blind therapy. All end point analyses used a last observation carried forward (LOCF) algorithm (the last available visit, from visit 3 onwards, served as an end point). For analyses of baseline efficacy and safety measures and changes from baseline to end point, only patients with a baseline (visit 2) and at least one postbaseline measure were included. In the computation of total scores on any individual scale, the total score was treated as missing if any of the individual items were missing. A one-sided lower 95% confidence limit for the difference in LOCF mean change in PANSS Total score for clozapine minus olanzapine was used in the primary efficacy analysis to demonstrate the noninferiority of olanzapine compared to clozapine. The inference was based on the lower limit of the confidence interval. A lower limit of 0 would indicate that olanzapine was statistically significantly superior to clozapine. A lower limit of 4 and 0 would indicate there was no difference between the two treatments, and noninferiority could be concluded, whereas a lower limit of 4 would indicate that no conclusion could be drawn regarding the noninferiority or superiority of olanzapine compared with clozapine. One-sided lower 95% confidence limits were also calculated for the secondary efficacy

4 Olanzapine vs. Clozapine in Schizophrenia BIOL PSYCHIATRY 55 variables, although no predefined criteria for determining noninferiority were stated. An analysis of variance (ANOVA) model with terms for treatment, geographic region, and treatment-by-geographic region interaction was used to evaluate continuous efficacy data. If the interaction was not significant (p.10) then it was removed and a model with terms for treatment and geographic region was used. One-sided lower 95% confidence limits based on the absolute difference in means were evaluated. In addition, the difference in least squares means were also evaluated and used to calculate the adjusted one-sided lower 95% confidence limit. Both observed cases (OC) and LOCF visitwise summary statistics were calculated. Significance tests for visitwise analyses were not performed since the primary outcome was to be evaluated based on the change from baseline to end point. Response rates were primarily calculated using the BPRS 1 7 total score and CGI-Severity score using an LOCF technique. A responder was defined a priori as any patient who achieved at least a 20% reduction in BPRS 1 7 total score from baseline to end point, plus either an end point CGI-Severity scale score of 3 or an end point BPRS 1 7 total score of 35, as defined and used by Kane et al (Kane et al 1988). Response rates (LOCF) were also evaluated for patients who achieved reductions in PANSS Total score of 20%, 30%, 40%, and 50% from baseline to end point. All statistical analyses for safety parameters are presented based on two-sided hypothesis tests. Categorical data (demographic variables, reasons for study discontinuation, treatmentemergent adverse events, solicited adverse events, incidence of EPS, and treatment-emergent abnormal laboratory analytes) were evaluated using a Pearson 2 test. Kaplan Meier survival curves of time to discontinuation were compared between treatment groups using the log-rank test. The categorical incidence of EPS based on rating scale definition was evaluated as follows. To assess treatment-associated psuedoparkinsonism, the proportion of patients with a Simpson Angus Scale total score of 3 at any postbaseline visit was calculated among those with a total score of 3 at baseline. To assess treatment-associated akathisia, the proportion of patients with a Barnes Akathisia Scale global score (item 4) 2at any postbaseline visit was calculated among those with a score of 2 at baseline. To assess treatment-associated abnormal dyskinetic movements, the proportion of patients with a score of 3 on any one of the AIMS items 1 through 7 or a score of 2 on any two of the AIMS items 1 through 7 at any postbaseline visit was calculated among those without either of these criteria at baseline. The latter definition is consistent with the crosssectional research diagnostic criteria suggested by Schooler and Kane (1982). All these definitions were made a priori and used in previous studies. Results Patient Characteristics A total of 180 patients (olanzapine: n 90; clozapine: n 90) were assigned to receive double-blind therapy. The Table 1. Patient Characteristics Olanzapine (n 90) Clozapine (n 90) n % n % Male Female White Other Schizophrenia subtype Catatonic Disorganized Paranoid Undifferentiated Residual Schizophrenia course Residual symptoms No residual symptoms Continuous In partial remission Other pattern reduced sample size was declared before unblinding and reflected a significant decline in recruitment once olanzapine had been approved for routine clinical use in Europe. The 180 randomized subjects decreased the power to declare noninferiority to 78% (instead of the planned 85%, based on 220 patients). The treatment groups were comparable with respect to baseline demographic and illness characteristics (Table 1). The majority of the patients were male (63.9%), white (96.1%), and 56.1% displayed a paranoid subtype of schizophrenia. The courses of illness, according to DSM- IV, were mainly continuous (51.1%) or episodic with interepisode residual symptoms (45.0%), and 72.6% had prominent residual negative symptomatology, based on the DSM-IV classification of longitudinal course of the disease. The mean (SD) age of the patient population was 38.6 (10.6) years with a mean (SD) age of onset of illness of 22.8 (5.6) years. The median (range) length of patient s current episodes was 187 (6 13,313) days, with 16 (17.8%) clozapine-treated patients and 9 (10.0%) olanzapine-treated patients having a current episode of less than 6 weeks duration. A large proportion of patients (43.4%) had more than 10 previous schizophrenic episodes before entry into the study. Patient s baseline scores on the PANSS and its subscales, the BPRS 1 7, and the CGI- Severity indicated that overall patients had severe and mixed symptomatology (positive and negative; Table 2). Patients also had a long history of illness and were documented by the investigators as being resistant to other antipsychotics.

5 56 BIOL PSYCHIATRY G.D. Tollefson et al Table 2. Mean Change in Efficacy Measures, Baseline to Endpoint (LOCF) Measure Therapy n Baseline Mean (SD) Change Mean (SD) Treatment effect a One-sided lower 95% confidence limit b PANSS Total Olanzapine (15.7) 25.6 (25.5) Clozapine (20.0) 22.1 (23.1) PANSS Positive Olanzapine (5.8) 6.8 (7.6) Clozapine (6.4) 6.4 (7.2) PANSS Negative Olanzapine (6.3) 7.1 (7.4) Clozapine (6.9) 5.6 (6.9) CGI-Severity Olanzapine (0.8) 1.1 (1.2) Clozapine (0.9) 0.9 (1.1) BPRS 1 7 Total Olanzapine (9.5) 15.2 (15.3) Clozapine (11.3) 14.0 (13.3) LOCF, last observation carried forward; N, number of patients with a baseline and at least one postbaseline measurement; PANSS, Positive and Negative Syndrome Scale; CGI-Severity, Clinical Global Impressions Severity of Illness Scale; BPRS, Brief Psychiatric Rating Scale. a Calculated as clozapine minus olanzapine. b Based on the absolute group mean change from baseline. Patient Disposition A total of 107 (59.4%) patients completed the 18-week, double-blind treatment period (olanzapine: 60.0%; clozapine: 58.9%). Completion rates after 6 weeks and 12 weeks of therapy for olanzapine-treated patients were 85.6% and 70.0%, respectively, and for clozapine-treated patients were 75.6% and 65.6%, respectively. Rates of discontinuation from the study because of adverse events were significantly lower for olanzapine compared to clozapine-treated patients [4.4% vs. 14.4%, 2 (1) 5.26, p.022]. There were no statistically significant differences between the two treatment groups for any other reason of discontinuation (lack of efficacy, 13.3% vs. 10.0%; patient decision, 10.0% vs. 4.4%; lost to follow-up, 2.2% vs. 2.2%; other, 10.1% vs. 10.1%). More patients discontinued early in the double-blind therapy period in the clozapine treatment group [Kaplan Meier survival estimates; log-rank 2 (1) 0.206, p.650; mainly owing to adverse events]. Dosage, Compliance, and Medication Use Only patients who received therapy beyond the 1-week titration period were included in the summary of exposure and modal drug dose (olanzapine: n 88; clozapine: n 83). For these patients, there were a total of 8802 patientdays of exposure to olanzapine and 8074 patient-days of exposure to clozapine. Table 3 shows the distribution of patients maximum daily dose and modal daily dose for each treatment group. A high incidence of clozapinetreated patients (44/83, 53.0%) received a maximum daily dose of mg, and the majority of olanzapinetreated patients (59/88, 67.0%) received a maximum daily dose of 25 mg. The mean (SD) daily dose for olanzapinetreated patients was 20.5 (2.8) mg/day (starting dosage of 15 mg/day) and for clozapine-treated patients was (108.7) mg/day (starting dosage of 200 mg/day after 1-week titration period). The numbers of patients using benzodiazepines at any time during the study were similar for the two treatment groups (olanzapine: 64.4%; clozapine: 53.3%). Investigation of benzodiazepine use during the washout period and at the time of randomization indicated that a similarly greater proportion of olanzapine patients were using benzodiazepines compared to clozapine (57.8% vs. 44.4%, Table 3. Summary of Maximum and Modal Daily Dosage During 18 Weeks Double-Blind Therapy for Patients Who Received Study Drug after the Initial Titration Period Maximum daily dose Modal daily dose Dose level n % n % Olanzapine (N 88) 15.0 mg mg mg mg mg Clozapine (N 83) 200 mg mg mg mg mg mg mg mg mg N, number of patients who received study drug after the initial titration period; n, frequency at each dose level.

6 Olanzapine vs. Clozapine in Schizophrenia BIOL PSYCHIATRY 57 Table 4. Weekly Changes in PANSS Total Score Using LOCF and OC Techniques Olanzapine (N 89) LOCF Week of therapy Mean (SD) Mean (SD) n Mean (SD) n Mean (SD) 1 week 4.2 (11.1) 2.9 (9.1) (11.1) (9.1) 2 weeks 9.4 (13.6) 9.2 (12.4) (13.8) (11.6) 3 weeks 14.6 (17.7) 13.5 (15.0) (18.1) (13.8) 4 weeks 17.1 (19.3) 15.4 (17.1) (19.6) (16.4) 6 weeks 20.7 (22.0) 20.5 (19.8) (20.4) (18.3) 8 weeks 20.8 (22.8) 20.5 (20.7) (19.9) (18.5) 10 weeks 23.0 (23.7) 21.0 (21.8) (20.5) (19.0) 14 weeks 24.0 (24.8) 21.5 (22.2) (19.7) (18.8) 18 weeks 25.6 (25.5) 22.1 (23.1) (20.5) (20.3) OC Clozapine (N 87) Olanzapine Clozapine PANSS, Positive and Negative Syndrome Scale; LOCF, last observation carried forward; OC, Observed; N, Number of patients with a baseline and at least one postbaseline measurement qualifying for LOCF analysis; n, number of patients with measurements at each visit eligible for OC analysis. respectively). Only seven olanzapine-treated patients and eight clozapine-treated patients initiated use of benzodiazepines during the study, and one olanzapine-treated patient used a benzodiazepine during the washout period but not during the study. Few patients used an anticholinergic agent (olanzapine: 4.4%; clozapine: 10.0%). The mean (SD) daily benzodiazepine medication use, expressed in lorazepam equivalents (mg/day), was not clinically different in the two groups (olanzapine: 4.2 (3.0) mg; clozapine: 3.2 (2.8) mg) nor was the mean (SD) daily anticholinergic medication use, expressed in benztropine equivalents (mg/day) (olanzapine: 1.3 (1.7) mg; clozapine: 1.8 (0.7) mg). Efficacy CHANGES IN EFFICACY MEASURES. There were no statistically significant differences between treatment groups on baseline efficacy measures, and although the PANSS Total scores were numerically different, they were not statistically significantly different (p.888). Both treatment groups showed significant within-group improvement (p.001) from baseline to end point (LOCF) in PANSS Total, PANSS Positive, PANSS Negative, BPRS 1 7 Total, and CGI-Severity scores (Table 2). PANSS Total scores were used to test the primary hypothesis that olanzapine was not inferior to clozapine in this study. Using the absolute observed group mean changes from baseline, the difference in means was 3.5 units in favor of olanzapine, and the one-sided lower 95% confidence limit was 2.2. Because this lower limit was 4 and 0, it indicated there was no clinical difference between the two treatments and noninferiority could be concluded. Using the adjusted group mean changes from baseline (obtained using the least squares means from the main effects model with terms for treatment and geographic region), the difference in means was 3.8 units in favor of olanzapine, and the one-sided lower 95% confidence limit was 1.9, leading to the same conclusion. Because of the apparent imbalance in baseline PANSS Total scores between the two treatment groups, an analysis of covariance was performed post hoc, where the covariate was the baseline PANSS Total score and the end point score was the dependent variable. The adjusted end point least squares means from this analysis were 80.3 for olanzapine and 83.4 for clozapine, with a one-sided 95% confidence interval for the difference (3.1 units in favor of olanzapine) being 3.7. Therefore, noninferiority could still be concluded. The visitwise mean change in PANSS Total score is shown in Table 4 using both an LOCF and OC method. The pattern of change over time was similar for the two treatment groups. Examination of mean changes from baseline for OC patients shows numerically greater changes during weeks 2 through 10 for clozapine, but for patients who receive treatment for 14 or 18 weeks there is a similar treatment effect in favor of olanzapine as calculated using the LOCF approach. RESPONSE RATES. Among the secondary study objectives, a similar proportion of olanzapine- (38.2%) and clozapine-treated patients (34.5%) achieved a response based on the combined BPRS 1 7 and CGI-Severity response definition (Table 5). Another definition of response, based on a 20%, 30%, 40%, and 50% change in PANSS Total score, yielded similar proportions of responders across the two treatment groups. The one-sided lower 95% confidence limits at the 30% and 40% criteria are 0, providing evidence of a significantly greater response with olanzapine. The incidence of patients showing no improvement or

7 58 BIOL PSYCHIATRY G.D. Tollefson et al Table 5. Response Rates Response definition Olanzapine (N 89) Clozapine (N 87) n (%) n (%) Treatment effect a One-sided lower 95% confidence limit BPRS 1 7 CGI-Severity b 34 (38.2) 30 (34.5) 3.7% 8.2% PANSS Total score 20% improvement 53 (59.6) 47 (54.0) 5.6% 6.7% 30% improvement 41 (46.1) 28 (32.2) 13.9% 1.9% 40% improvement 24 (27.0) 14 (16.1) 10.9% 0.8% 50% improvement 9 (10.1) 9 (10.3) 0.2% 7.7% N, number of patients with a baseline and at least one postbaseline measurement; n, number of responders based upon each response definition; BPRS, Brief Psychiatric Rating Scale; CGI-Severity, Clinical Global Impressions Severity of Illness Scale; PANSS, Positive and Negative Syndrome Scale. a Calculated as olanzapine minus clozapine. b Responder defined as a patient who achieved at least a 20% reduction in BPRS 1 7 total score from baseline to end point, plus either an end point CGI-Severity scale score of 3 or an end point BPRS 1 7 total score of 35. worsening of symptoms (defined as a percent change 0) was 11/89 (12.4%) for olanzapine-treated patients and 14/87 (16.1%) for clozapine-treated patients. Analysis of response rates controlling for gender and geographic region showed no evidence of differing patterns of response between treatments. Safety SPONTANEOUSLY REPORTED TREATMENT-EMER- GENT ADVERSE EVENTS. Table 6 shows the spontaneously reported adverse events that were reported by at least 5% of the patients in either treatment group or with a statistically significant difference in the rate of reporting (p.05) between treatment groups. The most frequently reported treatment-emergent adverse events in the olanzapine group were somnolence (13.3%), agitation (11.1%), and headache (11.1%). The most frequently reported treatment-emergent adverse events in the clozapine group were increased salivation (28.9%), somnolence (24.4%), constipation (18.9%), and nausea (11.1%). Throughout the 18 weeks of double-blind therapy, only one event (dry mouth) was reported statistically significantly (p.05) more often among the olanzapine-treated patients, whereas five events (increased salivation, constipation, nausea, dizziness, and tooth disorder) were reported statistically significantly more often among clozapine-treated patients. Other adverse events showed numerical differences between the treatment groups, the most notable being leukopenia, somnolence, and agitation. Leukopenia was reported for six patients (clozapine: five; olanzapine: one). The five clozapine-treated patients had leukocytes counts ranging from /L to /L (lower limit of normal range: /L), with only two out of five below the lower limit, and neutrophil counts ranging from /L to /L (lower limit of normal range: /L) with three below the lower limit. The one olanzapine-treated patient entered the trial with a low neutrophil count ( /L), which then normalized throughout the study, with the exception of one value after 1 week ( /L) considered as a laboratory error and consequently re-tested ( /L). Some investigators discontinued patients before they had reached the lower normal limit for these analytes. For instance, of the two clozapine-treated patients who discontinued for leukopenia after 2 months of treatment, only one had a neutrophil count below the normal limit, and in the one olanzapine-treated patient who discontinued after 5 weeks of therapy the neutrophil count was within the normal range. Table 6. Spontaneously Reported Treatment-Emergent Adverse Events with an Incidence of 5% in Either Treatment Group, or with a Statistically Significant Difference (p.05) between Treatment Groups Olanzapine (N 90) Clozapine (N 90) Event classification n % n % p value a Somnolence Agitation Headache Insomnia Constipation Weight gain Anxiety Rhinitis Dry mouth Vomiting Flu syndrome Asthenia Increased salivation Sweating Dizziness Fever Leukopenia Nausea Tooth disorder N, total number of patients randomized to each treatment group; n, number of patients reporting each adverse event. a Frequencies are analyzed using a Pearson 2 test with one degree of freedom.

8 Olanzapine vs. Clozapine in Schizophrenia BIOL PSYCHIATRY 59 Table 7. Solicited Adverse Events (AMDP-5) with a Statistically Significant Difference (p.05) in Incidence Olanzapine (N 89) Clozapine (N 86) Event classification n % n % p value a Drowsiness Hypersalivation Dry mouth Dizziness Increased perspiration Hypotonia Tardive dyskinesia AMDP-5, Association for Methodology and Documentation in Psychiatry; N, number of randomly assigned patients with a postbaseline AMDP-5 assessment; n, number of patients reporting each adverse event. a Frequencies are analyzed using a Pearson 2 test with one degree of freedom. SOLICITED TREATMENT-EMERGENT ADVERSE EVENTS (AMDP-5). Based on the AMDP-5 solicited adverse events scale, a statistically significantly greater proportion of clozapine-treated patients (p.05) experienced treatment-emergent drowsiness, hypersalivation, dizziness, increased perspiration, and hypotonia, whereas only the event terms of dry mouth and dyskinesia were reported significantly more often in olanzapine-treated patients (Table 7); however, of the five olanzapine-treated patients reported on the AMDP-5 to exhibit dyskinesia, only two patients met the criteria for treatment-emergent tardive dyskinesia (Schooler and Kane 1982) on the AIMS (one exhibited a probable withdrawal dyskinesia with evidence of a moderate dyskinesia first appearing in the first week, and the second experienced mild dyskinesia between weeks 4 and 10, which resolved spontaneously with continued treatment). The others only had transient mild or moderate dyskinetic episodes lasting from 1 to 4 weeks. It is doubtful that such symptoms represented tardive dyskinesia, as the usual duration criteria were not fulfilled. Rather these cases appeared to represent withdrawal dyskinesias. TREATMENT-EMERGENT EXTRAPYRAMIDAL SYMP- TOMS AS ASSESSED BY RATING SCALES. Categorical analyses of the Simpson Angus Scale, the Barnes Akathisia Scale, and the AIMS showed no statistically significant or clinically relevant differences between olanzapine and clozapine-treated patients in the incidence of treatmentemergent pseudoparkinsonism (7.5% vs. 10.5%), akathisia (9.7% vs. 11.3%), and dyskinesia (5.0% vs. 4.0%), respectively. Changes from baseline to end point in the Simpson Angus total score, the AIMS Non-Global total score (items 1 7), and the Barnes Global score (item 4) are shown in Table 8. There was a statistically significantly greater decrease in the Simpson-Angus total score for olanzapinetreated patients compared to clozapine-treated patients [F(1,161) 7.90, p.006]. WEIGHT AND ORTHOSTATIC BLOOD PRESSURE. There was no significant difference between treatment groups in the mean (SD) change from baseline to end point (LOCF) of body weight [olanzapine: 1.8 (5.0) kg; clozapine: 2.3 (4.9) kg; F(1,163) 0.39, p.534]. In the olanzapine-treated group, patients had a mean (SD) decrease in orthostatic blood pressure of 0.5 mm Hg (14.5) from baseline to end point, compared to 3.7 mm Hg (18.1) in the clozapine-treated group [F(1,161) 1.64, p.202). CLINICAL LABORATORY EVALUATION. Monitoring of leukocyte, neutrophil, and lymphocyte counts was performed extensively during the study, as specified in the clozapine monitoring requirements of the manufacturer. Comparisons between treatment groups showed no statistically significant differences from baseline to end point in leukocytes or neutrophils, although for lymphocytes there was a significantly greater baseline to end point decrease in clozapine-treated patients [F(1,159) 13.46, p.001]. Baseline and end point prolactin levels were obtained from 120 patients, 46 of whom (38.3%) had baseline prolactin levels above the normal range. The mean change from baseline to end point in prolactin levels [olanzapine: 0.18 nmol/l; clozapine: 0.14 nmol/l; F(1,109) 5.53, p.021] was significantly but not clinically different between the two treatment groups with olanzapine-treated patients demonstrating a greater increase compared to clozapine-treated patients. Five of the 17 discontinuations due to adverse events were laboratory related. Two clozapine-treated patients discontinued for leukopenia, after 8 and 10 weeks of Table 8. Mean Change in EPS Rating Scales, Baseline to Endpoint (LOCF) Baseline Change Measure Therapy n Mean (SD) Mean (SD) p value a Simpson-Angus total.006 Olanzapine (5.6) 3.2 (4.8) Clozapine (5.1) 1.4 (3.3) AIMS Non-Global total.630 Olanzapine (3.0) 0.8 (2.2) Clozapine (3.2) 0.7 (2.5) Barnes Global score.659 Olanzapine (1.0) 0.3 (0.9) Clozapine (1.0) 0.4 (1.0) EPS, extrapyramidal symptoms; LOCF, last observation carried forward; n, number of patients with a baseline and at least one postbaseline measurement; AIMS, Abnormal Involuntary Movement Scale. a p value is treatment effect from the main effects model with terms for treatment and geographic region using raw data.

9 60 BIOL PSYCHIATRY G.D. Tollefson et al treatment, although only one of the two had a neutrophil count ( /L) below the lower normal limit of the Lilly reference range ( /L). One olanzapine-treated patient discontinued after 5 weeks for a similar reason, despite a neutrophil count ( /L) above the lower normal limit. One clozapine-treated patient discontinued after 2 weeks for abnormal liver function test (ALT: 429 units/l; GGT: 798 units/l; alkaline phosphatase: 358 units/l) and one olanzapine-treated patient discontinued after 2 weeks for jaundice (AST: 361 units/l; ALT: 2786 units/l; GGT: 202 units/l; alkaline phosphatase: 189 units/l). Discussion This study represents the first direct head-to-head comparison of olanzapine and clozapine in a nonresponsive sample with schizophrenia. A significant strength was the large scale, prospective, double-blind nature of the trial. The study results confirmed that clozapine was effective in a treatment-resistant cohort as originally described by Kane et al (1988). Moreover, it demonstrated that olanzapine was at least as effective as clozapine in reducing the severity of overall psychotic symptoms and better tolerated. Thus, the results support early consideration of olanzapine in treatment-resistant schizophrenia based on a favorable risk-benefit profile. The nature of the olanzapine treatment effect, in such a sample, is concordant with the open-label reports of Martin et al (1997) and Dossenbach et al (in press), as well as interim results from a four-arm, blinded comparison of olanzapine, clozapine, risperidone, and haloperidol (personal communication, Jan Volavka); however, a similar magnitude of effectiveness was not apparent in a study by Conley et al (1998). In an effort to model aspects of the Kane design (Kane et al 1988), Conley followed 84 DMS-III schizophrenic patients who had failed an open-label run-in with haloperidol (10 40 mg/day) and were subsequently randomized to an 8-week, fixed-dose course of either olanzapine (25 mg/day) or chlorpromazine (1200 mg/day). Neither study arm demonstrated a high rate of a therapeutic response, defined as a 20% or greater reduction in BPRS and a posttreatment CGI less than 3 or a posttreatment BPRS score less than 35 (olanzapine: 7%; chlorpromazine: 0%). Of note, though, the results of Kane et al (1988) were clozapine 30% and chlorpromazine 4%, a seven-fold difference. Thus, the relative between-group comparisons may not be that disparate. This contrasting absolute response rate difference could have been attributed to one or more of the following design features: olanzapine dose, subject age, study design, severity of patient sample, completer s only analysis, or the length of the observational period. For example, it may have been that study participants at the Conley et al site represented an especially refractory cohort, perhaps by nature of that research center. Of note, only one of 103 subjects responded to haloperidol (10 40 mg) during the open 6-week qualifying phase. To that possibility, subjects also could have been previously treated with clozapine, since over half of those enrolled had previously not responded to an atypical agent, risperidone (Conley et al 1998). Thus, their response rates may not be directly comparable to either our study or that of Kane et al (1988). Relative to the duration of treatment, it is interesting to note that observed cases at weeks 7 and 8 began to diverge among the Conley sample favoring olanzapine. Subsequently, Conley et al (1998) rolled these double-blind subjects over to open-label olanzapine trial and subsequently noted a higher response rate (personal communication, Robert Conley). This may suggest that even among severely ill patients, responses may be delayed relative to those less severely ill. Conversely, this enhanced response rate may have only reflected the open nature of the follow-up. Although the impact of comparative dose selections is speculative, the utility of doses of olanzapine in excess of 25 mg has been suggested. Thus, it is plausible that such higher doses might have been associated with higher rates of response in the Conley sample. Last, it should be emphasized that the study methodologies across our study, Kane et al (1988), and Conley et al (1998) differed in both design and primary objectives. Most notably Conley et al (1998) did not include a clozapine arm. Thus, conclusions about the treatment responsivity of their cohort vis a vis another is limited. Several features of our methodology merit discussion. Our study was not intended to be a replicate of the Kane study. The primary purpose of our study was not to demonstrate that olanzapine was more effective than clozapine, but to show that olanzapine was not inferior to clozapine in treating refractory schizophrenic patients. To achieve this goal, only the population for which the use of clozapine was not restricted in Europe (i.e., resistant patients) could be studied. The definition of resistance was therefore based on clinical criteria obtained by history (defined as a lack of satisfactory clinical response to at least two previous oral neuroleptic treatments, each of a different chemical class, given for a duration of at least 6 weeks at an appropriate daily dosage). To accommodate ethical concerns in several Northern European countries, the appropriate daily dosage had to be restricted to at least 500 mg chlorpromazine equivalent. In addition, a sentence referring to the maximum tolerated daily dosage due to intolerable side effects had to be incorporated in the protocol, and investigators were asked to document it. Investigator sites were pooled within each country for

10 Olanzapine vs. Clozapine in Schizophrenia BIOL PSYCHIATRY 61 statistical modeling purpose, leading to satisfactory numbers investigating the homogeneity of treatment effects from a geographic region point of view. This is common practice when many investigator sites have to be used to recruit sufficient patient numbers in a reasonable amount of time. Because our inclusion/exclusion criteria were quite strict to try to obtain a true population of resistant patients, enrollment had to take place across many centers. The criteria for resistance did not specify whether it needed to be within the current episode or was to be based on the history of previously treated episodes, although the data suggest the latter was used. The mean baseline BPRS score of 60 for patients in this study is similar to the range of mean scores of obtained from patients who participated in previoius clinical trials of olanzapine; however, patients with treatment-resistant schzophrenia need not necessarily exhibit more severe symptoms, and thus the baseline scores obtained are fully compatible with treatment resistance. Although there are no formal rules applicable to washout conditions, the wash-out period may have been considered as too short in this study. Again, ethics and feasibility had to be taken into consideration. A longer period of wash-out would have been highly criticized by investigators and possibly rejected by Ethical Review Committees. Such a resistant population had already been treated with multiple conventional antipsychotic compounds. It is unlikely that additional drug-free days would have changed the final outcome. After several weeks of wash-out, patients would have likely been even more severely ill and would have demonstrated a higher PANSS score at baseline. Any possible carry-over effect potentially operative at the beginning of the study would have been equally distributed across the two study arms and not contributory to the final results. All but one adverse event (anxiety) causing discontinuation were not present at baseline and therefore were not likely attributable to a carry-over effect from previous treatment. The failure to complete rate, although high (around 40%), is consistent with that expected in clinical trials with the population targeted in this study (exclusively resistant schizophrenic patients). Considering the known pharmacologic and clinical profile of the two drugs (higher serotonin 2 than D 2 activity, as well as the low activity of the two drugs for D 2 receptors, with relatively low D 2 occupancy levels found in vitro and in vivo at clinical doses with positron emission tomography methods (Pilowsky et al 1996), it was anticipated that only a few patients would report EPS (Tran et al 1997). Earlier treatments with neuroleptics may also have had an impact on the emergence of EPS. The proportion of patients with emergent EPS was low in both groups. On all EPS scales the categorical incidence of EPS occurring at any point in time was numerically in favor of olanzapine. The observed results from the Simpson Angus Scale, favoring olanzapine, may have been attributed to the high incidence of hypersalivation in the clozapine group. To investigate this further, the Simpson Angus Scale analysis was repeated, omitting item 10 (salivation). The improvement in the olanzapine group was still marginally significant [F(1,161) 3.79, p.053]. One additional feature of this clinical study merits discussion: the choice of the dose range for both drugs that was determined to provide investigators flexibility to optimize the naturalistic dose best suited for each individual patient. As the study was performed in a resistant patient population, the dose of olanzapine up to 25 mg per day was explored. The dose range of clozapine was dictated by the then current European package labeling and was consistent with the current practice in Europe ( mg). The relatively more favorable rate of adverse events in the olanzapine group may have upwardly biased the modal dose of olanzapine relative to clozapine. In agreement was the fact that in the majority of olanzapine-treated patients (61.4%), the dose was increased to the maximum authorized level. The mean daily clozapine dose (303.6 mg) is similar to the mean daily clozapine dose (280 mg) usually prescribed in clinical practice based on data from four European countries: France, Italy, Spain, and UK (IMS data, first quarter 1998) in the same resistant schizophrenic population. It should be noted that the mean clozapine dosage in our study (303.6 mg) was somewhat less than that employed in the classic work by Kane et al (1988). Those investigators permitted a maximum dose of 900 mg/day; however, the mean modal dose appeared to have been closer to mg/day. These average differences reflect the rather divergent American and European perspectives on optimal dosing of clozapine (Pollack et al 1995). In their retrospective study, Pollack et al (1995) compared results from two groups of patients, an American high dose (mean mg at week 6) sample (n 84) with an Austrian lower dose (mean mg at week 6) sample (n 63). Results confirmed that the lower dose range group experienced superior clinical efficacy as measured by CGI change and tolerability; however, the absence of an adequate fixed dose comparison trial limits the ability to draw any firm conclusions as to the superior performance of one dose in one trial versus another dose in a second study. For the sake of argument, although a lower dose may be somewhat less effective during acute phase treatment, conversely it may well be better tolerated and thus associated with superior patient retention and the opportunity for superior therapeutic gains during maintenance.