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I nternational S uicide P revention T rial I nter S e PT Study Design Efficacy and Safety Results

C. I nternational S uicide P revention T rial I nter S e PT Study Design Efficacy and Safety Results. Rocco Zaninelli, MD Executive Director Clinical Research and Development Novartis Pharmaceuticals Corporation. C. InterSePT: Overview of Presentation. Study title and objective

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I nternational S uicide P revention T rial I nter S e PT Study Design Efficacy and Safety Results

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  1. C International Suicide Prevention TrialInterSePTStudy Design Efficacy and Safety Results Rocco Zaninelli, MD Executive Director Clinical Research and Development Novartis Pharmaceuticals Corporation

  2. C InterSePT: Overview of Presentation • Study title and objective • Study design • Statistical methods • Results • Examination of referral process • Conclusions from InterSePT

  3. C International Suicide Prevention Trial (InterSePT): Objective A prospective, randomized, international, parallel-group comparison of Clozaril®/Leponex® versus Zyprexa® in the reduction of suicidality in patients with schizophrenia or schizoaffective disorder who are at risk for suicide • Open-label study • Specific assessments were blinded

  4. C Study Design

  5. Starting dose during transition§ R A N D O M I Z A T ION Clozaril® 200 to 900 mg/day 12.5 mg BID Zyprexa® 5 to 20 mg/day 5 mg OD Baseline 1-wk intervals 2-wk intervals W 4 W 26 W 104 C Study Schematic CSR pp 26, 32 §Transition from previous medication ends at Week 4.

  6. C Patient Selection Criteria Patients with schizophrenia or schizoaffective disorder at high risk for suicide as documented by at least 1 of the following: • Suicide attempt within last 3 years • Hospitalization to prevent suicide in last 3 years • Moderate to severe suicidal ideation with depressive symptoms within 1 week of baseline • Moderate to severe suicidal ideation and self-harm command hallucinations within 1 week of baseline

  7. C Choice of Comparison Medication • Use of placebo unethical and inappropriate • Use of typical antipsychotic not considered current standard of care • Zyprexa® • Atypical antipsychotic; pharmacologically similar to Clozaril®§ • Lower rate of suicidality-related adverse events versus Risperdal®|| • Effective in psychosis and generally well tolerated • Available in most countries interested in conducting InterSePT § Bymaster et al, 1996. || Tran et al, 1996; Beasley et al, 1997.

  8. C Rationale for Open-Label Design Blinding would be compromised by • White blood cell count monitoring with Clozaril® • Different adverse event profiles

  9. C Primary Efficacy Endpoint Type 1 event or Type 2 event

  10. C Type 1 Event Definition • A significant suicide attempt or hospitalization due to imminent suicide risk (including increased level of surveillance) as determined by the blinded Suicide Monitoring Board (SMB)

  11. C Suicide Attempt Definition • Actions committed by a patient either with willful intent or as a response to internal compulsions or disordered thinking that put himself/herself at high risk for death

  12. C Type 2 Event Definition • Worsening of suicidality as measured by aCGI-SS-BP score of 6 or 7 (“much worse” or “very much worse”) OR • An implicit worsening of severity of suicidality as indicated by the occurrence of a suicide attempt or hospitalization to prevent suicide (Type 1 event)

  13. C Secondary Efficacy Assessments • Clinical Global Impression of Severity of Suicidality—Blinded Psychiatrist (CGI-SS-BP) • InterSePT Scale for Suicidal Thinking by Blinded Psychiatrist (ISST-BP)§ • Positive and Negative Syndrome Scale (PANSS)|| • Calgary Depression Scale (CDS)¶ • Covi Anxiety Scale(Covi)# § Lindenmayer et al, in press; || Kay et al, 1988. ¶ Addington et al, 1993; # Lipman, 1982.

  14. C Patient Site Database Blinded data SMB members Data Flow: Determination of Suicide Attempt/Hospitalization to Prevent Suicide Medical Monitor

  15. C Independent Suicide Monitoring Board (SMB) K. Ranga Rama Krishnan, MB, ChB Professor of Psychiatry and Behavioral Sciences Duke University Medical Center

  16. C SMB: Members • International experts in psychiatry and suicidology • Ranga Krishnan, MB.ChB (USA)—Chair • Isaac Sakinofsky, MD (Canada) • Hannele Heila, MD (Finland) • Not affiliated with investigative sites • Membership remained constant throughout the trial and each member participated in all meetings

  17. C SMB: Role • Blinded review of relevant data to determine whether a Type 1 event occurred • All deaths: to determine if cause was suicide • Potential suicide attempts: to determine their potential lethality (ie, true/serious attempts) • Hospitalizations related to suicidal behavior: to determine if caused by imminent risk of suicide

  18. C SMB: Material Used in Determination of Type 1 Events • Suicide attempt form • Rescue intervention form • Calgary Depression Scale • ISST • Clinical reports • History of suicidal behavior

  19. Potential events reviewed 577 SMB-determined Type 1 events 483 Suicide attempts 111 Hospitalizations to prevent suicide 372 C SMB: Cases Reviewed for Determination of Type 1 Events

  20. C Suicide Monitoring Board: Summary • Members were independent of any of the sites • Blinded review of every potential Type 1 event • Classification of each event based on a pre-defined process • Determinations of Type 1 events were unanimous

  21. C Statistical Methods

  22. C Primary Efficacy Analysis • Time-to-event analysis based on the WLW method§ • Used to analyze time-to-multiple-event data • Allows combination of different types of events • For InterSePT, used first Type 1 and first Type 2 event (stratified by country grouping) • WLW method established for revised primary endpoint by protocol amendment §Wei, Lin, and Weissfeld. 1989.

  23. C Supportive Analyses • Cox’s proportional hazards analysis • Explanatory variables included drug treatment, number of suicide attempts, current substance/alcohol abuse, country grouping, gender, and age groups • Kaplan-Meier estimates of cumulative probabilities • Analysis of clinical variables based on last-observation-carried-forward (LOCF)

  24. C Sample Size Protocol p. 48 • Statistical assumptions • Randomization ratio 1:1 • Log-rank test with alpha = 5% (2-sided) • Power: 80% • Estimated 45% of Clozaril® and 55% of Zyprexa® patients with at least 1 Type 1 event by the end of 2 years • Total of 381 events (762 patients) • Allowing for 15% dropout rate, ~ 900 patients to be randomized

  25. C InterSePT Results Characteristics of Study Population

  26. 3 C InterSePT Study Centers and Dates CSR p. 17 67 centers 11 countries First patient first visit March 19, 1998 Last patient last visit February 14, 2001 Database lock June 9, 2001

  27. C Patient Disposition CSR table 7-1 Patients, n (%) Disposition Clozaril® Zyprexa® Screened 1,065 total Randomized (ITT) 490 (100) 490 (100) Treated 479 (97.8) 477 (97.3) Completed 298 (60.8) 302 (61.6) Discontinued 192 (39.2) 188 (38.4) Complete 1º efficacy data 73 (14.9) 88 (18.0) “True” dropouts 119 (24.2) 100 (20.4)

  28. C Demographics at Baseline CSR T7.4 Patients, n (%) Clozaril® Zyprexa®Demographic parameter N = 490 N = 490 Age, yr18 - 32 168 (34.3) 178 (36.3) 33 - 44 216 (44.1) 204 (41.6) 45 106 (21.6) 108 (22.0) Mean age at onset, yr 24.9 ± 8.6 24.4 ± 8.3 Male 301 (61.4) 301 (61.4) RaceCaucasian 356 (72.7) 337 (68.8) Black 65 (13.3) 86 (17.6) Oriental 6 (1.2) 7 (1.4) Other 63 (12.9) 60 (12.2) ITT population.

  29. C Diagnosis and History of Treatment Resistance CSR T7.4 Patients, n (%) Clozaril® Zyprexa® N = 490 N = 490 Diagnosis Schizophrenia 300 (61.2) 309 (63.1) Schizoaffective disorder 190 (38.8) 181 (36.9) Treatment resistant 135 (27.6) 128 (26.1)

  30. C Clinical Characteristics at Baseline CSR table 7-1 Mean ± SD Characteristics Clozaril® Zyprexa® CGI-SS-BP§ 2.2 ± 1.0 2.2 ± 1.0 ISST-BP 7.4 ± 5.7 7.3 ± 5.7 Lifetime suicide attempts 3.6 ± 7.5 3.2 ± 4.5 Lifetime hospitalizations 3.7 ± 7.7 3.2 ± 4.8to prevent suicide PANSS-T 84.8 ± 21.1 82.6 ± 20.9 CDS 9.8 ± 5.9 9.9 ± 5.9 Covi Anxiety Scale 3.8 ± 2.7 3.9 ± 2.7 §2 = Mildly suicidal; 3 = Moderately suicidal.

  31. C Study Discontinuations CSR T7-1 Patients, n (%) Clozaril® Zyprexa®Discontinued forN = 490 N = 490 Withdrawn consent 50 (10.2) 49 (10.0) Adverse event 41 (8.4) 33 (6.7) Lost to follow-up 33 (6.7) 39 (8.0) Protocol violation 29 (5.9) 20 (4.1) Administrative reasons 23 (4.7) 27 (5.5) Death 8 (1.6) 5 (1.0) Unsatisfactory effect on psychosis 5 (1.0) 9 (1.8) Abnormal lab value 2 (0.4) 0 (0.0) Abnormal procedure result 1 (0.2) 0 (0.0) Unsatisfactory effect on suicide risk 0 (0.0) 6 (1.2) Total (380, 39%) 192 (39.2) 188 (38.4)

  32. C Study Medication: Total Daily Dose Clozaril® Zyprexa® N = 477 N = 477 Mean ± SD274 ± 155 17 ± 6 Median 262 17 Range 13 - 725 3 - 41

  33. C InterSePT Results Efficacy Results Primary Endpoint

  34. C Patients Experiencing SMB-Determined Type 1 Events: Suicide Attempts and Hospitalizations CSR Table 9-5

  35. Distribution of Patients by Number of Suicide Attempts or Hospitalizations to Prevent Suicide

  36. C Patients Experiencing Type 2 Events:Worsening of Suicidality, Suicide Attempt, Hospitalization to Prevent Suicide CSR Table 9-5 161 120 ® ®

  37. C Results of WLW and Cox’s Analyses CSR Table 9-1 Hazard ratio 95% CI P value WLW .031 Cox’s proportional hazard analysis§ Type 1 0.74 0.57, 0.96 .021 Type 2 0.76 0.60, 0.97 .026 § Protocol specified full model.

  38. C Kaplan-Meier Estimates of Cumulative Probabilities of a Type 1 or Type 2 Event Type 1 Type 2 37% 32% 28% 24% Clozaril® Zyprexa®

  39. Cox’s Analyses of Type 1 Events by Subgroups Schizophrenia Schizoaffective Treatment resistant Non-treatment resistant North America Rest of World Male Female White Non-White Age 18 - 32 33 - 44 > 44 Hazard ratio (95% CI) 0.30 0.37 0.45 0.55 0.67 0.82 1 1.22 1.49 favoring Zyprexa®--> <------------- favoring Clozaril® --------------

  40. C InterSePT Results Efficacy Results Secondary Efficacy Assessments

  41. C Change in Severity of SuicidalityCGI-SS-BP at Week 104 CSR Table 9.3-17 P = .280 < < <

  42. C LS Mean Change From BaselineISST-BP, PANSS-T, CDS and Covi at Week 104 CSR Table 9-10 P = .578 P = .767 P = .399 P = .359

  43. C LS Mean Daily Dose (mg) of Concomitant Psychotropic Medications Least square mean (± SE) Medications Clozaril® Zyprexa®P value Antipsychotics§ 2.1 ± 0.3 3.8 ± 0.3 < .001 Antidepressants|| 16.7 ± 1.1 20.7 ± 1.0 .001 Sedatives/ 6.3 ± 0.6 10.1 ± 0.6 < .001anxiolytics¶ Mood stabilizers# 487.3 ± 43.2 620.6 ± 39.9 .011 § Haloperidol, || fluoxetine, ¶ diazepam, # carbamazepine equivalents.

  44. C Safety

  45. C Incidence of Adverse Events and Serious Adverse Events PTT 10.1-1 Patients, n (%) Clozaril ® Zyprexa® N = 479 N = 477 P value AEs 443 (92.5) 450 (94.3) .297 SAEs 231 (48.2) 235 (49.3) .796 No cases of agranulocytosis, myocarditis, or cardiomyopathy in the Clozaril group1 case of cardiomyopathy in the Zyprexa group

  46. C Clozaril® Adverse Events of Interest Patients, n (%) PTT 10.1-2 Clozaril® Zyprexa®Adverse event N = 479 N = 477 Salivary hypersecretion 229 (47.8) 28 (5.9) < .0001 White blood cell decrease 28 (5.8) 4 (0.8) < .0001 Constipation 120 (25.1) 46 (9.6) < .0001 Weakness 36 (7.5) 11 (2.3) < .001 Postural hypotension 21 (4.4) 1 (0.2) < .0001 Convulsions 12 (2.5) 2 (0.4) .012 P value§ § Fisher’s exact test.

  47. C Zyprexa® Adverse Events of Interest Patients, n (%) PTT 10.1-2 Clozaril® Zyprexa®Adverse event N = 479 N = 477 Weight increased 150 (31.1) 265 (55.6) < .0001 Dry mouth 26 (5.4) 43 (9.0) .034 Diabetes mellitus NOS 16 (3.3) 21 (4.4) NS Asthma 5 (1.0) 19 (4.0) .004 Laceration 2 (0.4) 19 (4.0) < .001 Epistaxis 0 5 (1.0) .031 P value§ Statistically significant differences between groups. NOS = Not otherwise specified § Fisher’s exact test.

  48. C Neuropsychiatric Adverse Events PTT 10.1-2 Clozaril® Zyprexa®Adverse event N = 479 N = 477 Depression 137 (28.6) 173 (36.3) .013 Suicidal ideation 125 (26.1) 153 (32.1) .046 Suicide attempt 37 (7.7) 66 (13.8) .002 Drug abuse 4 (0.8) 14 (2.9) .018 Tension 3 (0.6) 11 (2.3) .034 Mood disorder 0 8 (1.7) .004 Insomnia 96 (20.0) 155 (32.5) < .0001 Akathisia 21 (4.4) 39 (8.2) .016Somnolence 220 (45.9) 118 (24.7) < .0001Dizziness 129 (26.9) 59 (12.4) < .0001Dysarthria 23 (4.8) 2 (0.4) < .0001Syncope 15 (3.1) 5 (1.0) .039 Patients, n (%) P value§ § Fisher’s exact test.

  49. C Deaths PTT 10.1-2 Patients, n Cause of death Clozaril® Zyprexa® Suicide 5 (+1) 3 (+1) Cardiac arrhythmia 2 1 Coronary artery disease 1 Myocardial infarction 1 Cardio-respiratory arrest 2 Stroke 1 Pulmonary embolism 1 Car accident 1 Lymphoma 1 Carcinoma 1 Total 13 9

  50. Examination of the Process of Referral of Potential Type 1 Events to the SMB

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