# Presentation: 730640

## International Suicide Prevention Trial InterSePT Study Design Efficacy and Safety Results

**Rocco Zaninelli, MD**
**Executive Director**
**Clinical Research and Development**
**Novartis Pharmaceuticals Corporation**

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## InterSePT: Overview of Presentation

**Study title and objective**
**Study design**
**Statistical methods **
**Results**
**Examination of referral process**
**Conclusions from InterSePT**

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## 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**

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## Study Design

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## Study Schematic

**Study Schematic**

**§Transition from previous medication ends at Week 4.**

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**CSR pp 26, 32**

**Notes:**
1- Clinician had the flexibility to manage the patient’s other psychotropic medication to ensure patient safety
2- Mention recommended dosage only (not what actually happened)
3- Mention open-label design

Q2. What was the basis of the dosage recommendation for both treatment groups?
Q28. How was the clinical care separated from the blinded raters at the centers?  

## 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**

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## 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**

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**§ Bymaster et al, 1996.**
**|| Tran et al, 1996; Beasley et al, 1997.**

**Notes:**
Indicate that Zyprexa is not approved for suicidality.

## Rationale for Open-Label Design

**Blinding would be compromised by **
**White blood cell count monitoring ****with Clozaril****®**
**Different adverse event profiles**

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## Primary Efficacy Endpoint

**or **
**Type 2 event**

**Primary Efficacy Endpoint**

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## 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)**

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## 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**

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**Notes:**
Q24. What was the collaboration with the FDA regarding the definition of suicidality? 

## Type 2 Event

**Definition**** **
**Worsening of suicidality as measured by a****CGI-SS-BP score of 6 or 7 (“much worse” or ****“very much worse”)**

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**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)**

**Notes:**
During the early part of InterSePT, there was concern that not enough Type 1 events would occur, thereby jeopardizing the primary comparison.
The Type 2 Event was therefore introduced into InterSePT as part of the revised primary endpoint.

## 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)****#**

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**§ Lindenmayer et al, in press; || Kay et al, 1988.**
**¶ Addington et al, 1993; # Lipman, 1982.**

**Notes:**
Mention that CGI-SS-BP is used for baseline severity and change in severity.

Q22. a) Is there an item concerning hopelessness in the ISST?
         b) Was hopelessness an item in any of the scales? Did you do an item    analysis?	

Q27. How was rater's reliability maintained across sites? (training, consistency at baseline, re-testing during the study?)	

Q47. Has the ISST been validated?

## Data Flow: Determination of Suicide Attempt/Hospitalization to Prevent Suicide 

**Medical Monitor**

**Data Flow: Determination of Suicide Attempt/Hospitalization to Prevent Suicide **

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**Notes:**
Novartis (essentially) blinded to treatment grouping.
Only one case in which unblinded patient data reached SMB.

Q16. Was the medical monitor in the CRO blinded to the data? 	

Q17. Did the CRO filter any cases in the PEP’s that were presented to the SMB?
    A. No.
Q26. How was the SMB monitored to ensure their blindness? 	
    A. Not necessary since SMB received only blinded data.
Q33. How did we distinguish a gesture from a true attempt?	
    A.  Distinctions based on consensus decisions based on all available data.

## Independent Suicide Monitoring Board (SMB)

**K. Ranga Rama Krishnan, MB, ChB**
**Professor of Psychiatry and ****Behavioral Sciences**
**Duke University Medical Center**

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## 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**

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## 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**

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## 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**

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## SMB: Cases Reviewed for Determination of Type 1 Events

**Potential events reviewed****	****577**
**SMB-determined Type 1 events****	****483**
**Suicide attempts****	****111**
**Hospitalizations to prevent suicide****	****372**

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## 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**

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## Statistical Methods

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## 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.**

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**Notes:**
1- Formally the WLW method first analyzed the data by combining the two types of events to provide a test of overall significance of treatment difference between the 2 groups.
2- Prespecified analysis
3- Accepted by FDA

Q9. Please elaborate on the WLW statistical analysis. 

## 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) **

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## Sample Size 

**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**

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**Protocol p. 48**

**Notes:**
Log rank test used in original design.

Q35. Were there randomization blocks to ensure similar number of patients in each site. If yes, how large? Was the randomization assignment made centrally?

## InterSePT Results

**Characteristics of Study Population**

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## InterSePT Study Centers and Dates

**67 centers**
**11 countries**
**First patient first visit****	****March 19, 1998**
**Last patient last visit****	****February 14, 2001**
**Database lock****	****June 9, 2001**

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**CSR p. 17**

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**Notes:**
40% of patients were recruited at US sites.

## Patient Disposition

**	****	****                                                       ****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)**

** ****CSR table 7-1**

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**Notes:**
Q30. What were the baseline characteristics of a) the screen failures and b) the small proportion of subjects that dropped out between randomization and administration of first dose?	

Q34. a) What information was collected on retrieved dropouts?  
         b) What was the meantime to dropout?
          c) Are there demographic and clinical difference between completer and    dropout?	
Q36. How did we define drug compliance?  How did you measure compliance?
Q70. How many patients switched treatment drugs?

## Demographics at Baseline

**Age, yr****	****18 - 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)**
**Race     ****	****Caucasian****	****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)**

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**	****	****                       ****Patients, n (%)**
**	****	****Clozaril****®****	****Zyprexa****®****Demographic parameter****	****N = 490****	****N = 490**

**CSR T7.4**

**ITT population.**

**Notes:**
Q50. What were the ‘other’ races?	
Q51. Was efficacy outcome influenced by demographic variables?	
Q69. What was the mean duration of illness?

## Diagnosis and History of Treatment Resistance

**Diagnosis**
**	****Schizophrenia****	****300****	****(61.2)****	****309****	****(63.1)**
**	****Schizoaffective disorder****	****190****	****(38.8)****	****181****	****(36.9)**
**Treatment resistant****	****135****	****(27.6)****	****128****	****(26.1)**

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**	****	****                        ****Patients, n (%)**
**	****	****Clozaril****®****	****Zyprexa****®****	****	****N = 490****	****N = 490**

**CSR T7.4**

**Notes:**
Q1. In the two comparative cohorts, what was the distribution of patient with a history of substance abuse at baseline? 	

Q11. Were the groups comparable with respect to known risk factors for suicidality? 	
Q20. What is the relationship of treatment resistance and the frequency of Type 1 events?	

Q43. Is there a difference in the frequency of substance abuse between patients with schizophrenia and schizoaffective disorder in each group?	

## Clinical Characteristics at Baseline

**	****                         ****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 ± 4.8****to 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**

** ****CSR table 7-1**

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**§2 = Mildly suicidal; 3 = Moderately suicidal.**

**Notes:**
Q12. What was the number of patients with greater than 5 suicide attempts in both groups at baseline? 

## Study Discontinuations

**	****                         ****Patients, n (%)**
**	**** ****Clozaril****®****	****Zyprexa****®****Discontinued for****	****N = 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)**

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**CSR T7-1**

**Notes:**
Q32. What are the reasons for dropout in each group during the first 6 months?	
Q48. Were there differences in discontinuation rates across countries?	

Q52. Characteristics of patients who dropped out due to unsatisfactory effect on suicide risk?	

## Study Medication: Total Daily Dose

**	**** ****Clozaril****®****	****Zyprexa****®**** ****	****N = 477****	****N = 477**
**Mean ****± SD****	****274 ± 155****	****17 ± 6**
**Median****	****262****	****17**
**Range****	****13 - 725****	****3 - 41**

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**Notes:**
Q83. Compare the distribution of prescribed daily dose of study med for all patients and for completers.	

## InterSePT Results

**Efficacy Results**
**Primary Endpoint**

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## Patients Experiencing SMB-Determined Type 1 Events: Suicide Attempts and Hospitalizations

**CSR Table 9-5**

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**Notes:**
Q15. What was the suicidality status as identified by PI and BP in patients with attempts at the time of the attempt?  (What was the change in SS from baseline to attempt?)	
Q19  What was the “treatment resistant” status in the patients who completed suicide?
Q42  How many patients in each group with a Type I event also had a suicide attempt(s) in the 36 months prior to study start? 
Q45. a) What was the mean duration of hospitalization for Type 1 events?  b) How many patients in each group were hospitalized for reasons not related to suicidality?
Q55  a) What was the number of SMB-determined Type-I event in each treatment group? b) What is the distribution of patients by frequency of Type I events?  
Q62 a) Were all suicide attempts recorded as AEs captured as Type I events? 
 b) Was there a difference between the groups?  
Q63  Are all AE cases of suicide events captured as type I events?
Q64  How many patients in each group had more than one SMB-determined Type I event?	
Q77  How many Type I events were there per patients in each group? 	

## Distribution of Patients by Number of Suicide Attempts or Hospitalizations to Prevent Suicide

## Patients Experiencing Type 2 Events:Worsening of Suicidality, Suicide Attempt, Hospitalization to Prevent Suicide

**CSR Table 9-5**

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**120**

**161**

- ®

- ®

## Results of WLW and Cox’s Analyses 

**	****	****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**

**CSR Table 9-1**

**§ Protocol specified full model.**

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**Notes:**
. 
Q25. Why was the country rather than the site used as stratum?
Q49. What were the country groupings that were used in the full Cox model?
Q53. a) Was race included in the Cox model?
          b) Did you do any analysis by race?	
Q76. WLW and Cox Proportional hazard Model after excluding patients who were Clozaril (Tx)/Olanzapine (ConMed) or Zyprexa (Tx/Clozapine (ConMed)
Q78. WLW and Cox Proportional Hazard Model after excluding Retrieve Drop Out (RDO) data.	
Q79. Subgroup primary analyses by gender, by treatment resistance, race (white and non-white), and by age group.
Q80. Is there a difference between treatment groups with regard to time to Type 1 event using Cox Proportional Hazard Model including Country-by-treatment interactions.	
Q81. What are the results from the WLW analysis based on Type 1 and Type 2 based on Blinded Psychiatrist (BP) data?	

## Kaplan-Meier Estimates of Cumulative Probabilities of a Type 1 or Type 2 Event

**Kaplan-Meier Estimates of Cumulative Probabilities of a Type 1 or Type 2 Event**

**32%**

**24%**

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**37%**

**28%**

**Clozaril****®**

**Zyprexa****®**

**Type 1**

**Type 2**

**Notes:**
Q29. Mean time to Type 1 event?
    A. CLZ 155.2 ± 154.4; median 87 days (n = 102)
         ZYP 205.9 ± 202.6; median 127 days (n = 141)
         Wilcoxon RS test  P = .123

Q39. Comment on the fact that most events occurred in the first 6 months of treatment where there is no difference in treatment effect between groups.	
Q46. Imputation bias (Dr Fleming):  “Three hundred and ten people, which is about half of the complement of this group, were only followed for part of the time. And yet, you’re counting all of those people the same as though they had been followed the whole time and were free of an event the whole time.  That’s terribly biased.  So what you’ve done is you’ve done a Kaplan- Meier estimate to impute what they actually had.  But this analysis doesn’t account for that.  This analysis counts anybody with partial follow up as a full success.”	

## Cox’s Analyses of Type 1 Events by Subgroups

**0.30**

**0.37**

**0.45**

**0.55**

**0.67**

**0.82**

**1**

**1.22**

**1.49**

**Non-treatment resistant**

**Treatment resistant**

**Schizophrenia**

**Schizoaffective**

**Female**

**Male**

**North America**

**Rest of World**

**Age 18 - 32**

**Non-White**

**White**

**33 - 44**

**> 44**

**Hazard ratio (95% CI)**

- <------------- **favoring Clozaril****®** --------------

**favoring Zyprexa****®**** **-->

## InterSePT Results

**Efficacy Results**
**Secondary Efficacy Assessments**

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## Change in Severity of SuicidalityCGI-SS-BP at Week 104

**C**

**CSR Table 9.3-17**

**<**

**<**

**<**

***P***** = .280**

**Notes:**
Q82  What is difference between the groups with regard to Mean Change from baseline to Type I event/ EOS in PANSS-T, CGI-SS-BP, ISST, and CDS between Eventer and Non-Eventer?

## LS Mean Change From BaselineISST-BP, PANSS-T, CDS and Covi at Week 104

** **

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**CSR Table 9-10**

***P***** = .359**

***P***** = .399**

***P***** = .578**

***P***** = .767**

## 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****	****< .001****anxiolytics****¶**
**Mood stabilizers****#****	****487.3 ± 43.2****	****620.6 ± 39.9****	****   .011**

**§ Haloperidol, || fluoxetine, ¶ diazepam, # carbamazepine equivalents.**

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**Notes:**
Q10. How many patients in each group used lithium and what was the mean dosage?  What was the mean daily dose for patients with/without Type 1/Type 2 events?  (mean daily dose up to event)	
Q56. How many patients in each group used lorazepam and what was the mean dosage?  What was the mean daily dose for patients with/without Type 1/Type 2 events?  (mean daily dose up to event)	
Q57. How many patients in each group used typical /atypical antipsychotics and what was the mean dosage?  What was the mean daily dose for patients with/without Type 1/Type 2 events?  (mean daily dose up to event)	
Q58. Does this include PRN use?	
Q59. What was the pattern of use for each class of  concomitant medication?
Q71. What was the mean number of concomitant psych meds per patient during the study?	
Q72. What was the mean number of concomitant psych meds of each class in patients with/without Type 1/Type 2 events? 	
Q73. What was the total mean daily dose of antipsychotic med per patient per treatment group (i.e., treatment drug + concomitant antipsychotic, in haloperidol equivalents)?	
Q75. Mean daily dose vs. time plot for completers by psychotropic class.	

## Safety

**C**

**Notes:**
Q6. What was the change in relative weight? 
Q8. Was there an association between any of the events that relate to diabetes and weight change?

## Incidence of Adverse Events and Serious Adverse Events

**	****                                       ****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**

**PTT 10.1-1**

**No cases of agranulocytosis, myocarditis, or cardiomyopathy in the Clozaril group****1 case of cardiomyopathy in the Zyprexa group**

**C**

**Notes:**
Q37. Was severity of AEs rated? 
Q38. Report the number of SAEs in each group 

## 					 	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

**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**

**Clozaril****®**** Adverse Events of Interest**

**Patients, n (%)**

***P *****value*****§***

**C**

**§ Fisher’s exact test.**

**PTT 10.1-2**

**Notes:**
Q5. How many patients in each group had hyperglycemia as an AE or a clinically notable laboratory parameter?	
Q6  What was the change in relative weight in the treatment groups?
Q7. Was the effect of the treatments on QTc measured?	
Q8  Was there an association between any of the events that relate to diabetes and weight change?	
Q44. Did you observe any treatment-emergent diabetes mellitus in the Zyprexa group?

## 					 	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

**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**

**Zyprexa****®**** Adverse Events of Interest**

**Patients, n (%)**

**C**

**Statistically significant differences between groups.**
**NOS = Not otherwise specified**
**§ Fisher’s exact test.**

**PTT 10.1-2**

***P *****value*****§***

**Notes:**
Q60. Comment on occurrence of asthma in light of recent reports of pulmonary disease with atypical antipsychotics?	

Q61. Is epistaxis mentioned in the labeling for Zyprexa?	

## 					 	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)	.016Somnolence	220 (45.9)	118 (24.7)	< .0001Dizziness	129 (26.9)	  59 (12.4)	< .0001Dysarthria	23 (4.8)	  2 (0.4)	< .0001Syncope	15 (3.1)	  5 (1.0)	.039

**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)****	****.016****Somnolence****	****220 (45.9)****	****118 (24.7)****	****< .0001****Dizziness****	****129 (26.9)****	****  59 (12.4)****	****< .0001****Dysarthria****	****23 (4.8)****	****  2 (0.4)****	****< .0001****Syncope****	****15 (3.1)****	****  5 (1.0)****	****.039**

**Neuropsychiatric Adverse Events**

**Patients, n (%)**

***P***** value****§**

**§ Fisher’s exact test.**

**C**

**PTT 10.1-2**

**Notes:**
Q64. a) What does mood disorder as an AE mean?
b) How many patients had an AE of mood disorder?
c) Was there an equal distribution between the treatment groups?
d) Which preferred terms were coded (PI term) to mood disorders?	

Q65. Were patients who experienced convulsions taking anti-seizure medications which were also mood stabilizers?

## 				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

**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**

**Deaths**

**Patients, n**

**C**

**PTT 10.1-2**

**Notes:**
Q13. What were the methods of completed suicide in the two groups? 	
Q14. a) What was the suicidality status as identified by PI in patients with completed suicide at the time of the attempt?  What was the change in SS from baseline to attempt?  b) What was the suicidality status as identified by the BP in patients with completed suicide at the time of the attempt?  What was the change in SS from baseline to attempt?
Q18. How many of the deaths were considered drug related?	
Q19. What was the “treatment resistant” status in the patients who completed suicide?	
Q23. How do you explain the difference in suicide rates between treatment groups?	
Q41. Was there any pattern as to when completed suicides and suicide attempts occurred?	
Q66. a) What was the mean dose of study drug for those patients who committed suicide?  b) What was the mean dosage of psychotropic medication (by class)?
Q67. Mean time to suicide? 
Q68. How do we know that the car accident was not a suicide?	
Q74. What were the baseline and last available values for the PANSS-T, CDS, ISST, CGI-SS-BP and Covi of patients who committed suicide?

## Examination of the Process of Referral of Potential Type 1 Events to the SMB

## InterSePT Design: Potential Bias in Referrals to SMB

**Medical Monitor**

**InterSePT Design: ****Potential Bias in Referrals to SMB**

**C**

**Notes:**
Novartis (essentially) blinded to treatment grouping.
Only one case in which unblinded patient data reached SMB.

Q16. Was the medical monitor in the CRO blinded to the data? 	

Q17. Did the CRO filter any cases in the PEP’s that were presented to the SMB?
    A. No.
Q26. How was the SMB monitored to ensure their blindness? 	
    A. Not necessary since SMB received only blinded data.
Q33. How did we distinguish a gesture from a true attempt?	
    A.  Distinctions based on consensus decisions based on all available data.

## Method to Review the Process of Referral of Potential Type 1 Events to SMB

**Assumption: referral bias limited to all cases **_**not**_** referred to SMB (N = 701)**
**Search term dictionary developed based on AE terms and Query and Comment databases**
**Search term dictionary applied to each case **
**CRFs from term-matched cases were reviewed:**
**Whether PI was queried regarding occurrence of suicidal behavior**
**PI’s response**
**Whether AE was potentially related to suicidal behavior**

## Review of Referral Process:Summary of Findings

**5**

**Number of cases with occurrence of potential suicidal behavior**** **

**279**

**Number of cases with at least one search-term match**** **

**701**

**Total number of non-referred cases**

**These results indicate that, although the PIs were **
**unblinded, they acted without bias**

**(3 Clozaril, 2 Zyprexa)**

## Conclusions From InterSePT (1)

**During InterSePT, treatment with Clozaril****®**** compared with Zyprexa****®**** was associated with a 26% reduction of risk for suicide attempts and hospitalizations to prevent suicide.**
**For all subgroups examined, there was a high degree of consistency in the reduction of risk for suicidal behavior in the Clozaril group compared to the Zyprexa group. **

**C**

**Notes:**
Q3. Is the clozapine effect on suicidality dose-related? What will be the suggested maximum dose for targeting suicidality?	

Q4. Influence of diagnosis of schizoaffective disorder and schizophrenia on outcome?	

Q21. What was the confidence interval range for an NNT of 12.5?	

Q31. Is the effect on suicidality a class effect?	

Q40. Benefit - risk assessment (risk of attempting suicide vs. risk of agranulocytosis)	

## Conclusions From InterSePT (2)

**The reduction of risk in the Clozaril group appears not to be attributable to a greater effect on psychotic or depressive symptoms or to greater use of concomitant psychotropic medications.**
**Adverse event profiles for both study drugs were generally consistent with previous experience and current product labeling.**
**The open-label design was not associated with biased assessments by the PIs.**

**C**

**Notes:**
Q3. Is the clozapine effect on suicidality dose-related? What will be the suggested maximum dose for targeting suicidality?	

Q4. Influence of diagnosis of schizoaffective disorder and schizophrenia on outcome?	

Q21. What was the confidence interval range for an NNT of 12.5?	

Q31. Is the effect on suicidality a class effect?	

Q40. Benefit - risk assessment (risk of attempting suicide vs. risk of agranulocytosis)	

## Overall Conclusion

**	****The results of InterSePT show that Clozaril****®**** is effective and safe in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder.**

**C**