Conditions: Bipolar Disorder
Keywords: Bipolar I Disorder (current or most recent episode manic). Children and adolescents aged 10 to 17 years.
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 171
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if ziprasidone is safe and effective for the treatment of children and adolescents (ages 10-17) with bipolar I disorder (manic or mixed).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: placebo oral capsules intervention 2: ziprasidone oral capsules
Intervention descriptions: intervention 1: Placebo matching the oral ziprasidone capsules of 20,40, 60 and 80 mg in strength. Subjects will be dosed for 4 weeks using a flexible dosing design. Dosing is stratified based on weight, with subjects \<45 kg having a target dose range of 60-80 mg/day and subjects \>/= 45 kg having a target dose range of 120-180 mg/day. intervention 2: Oral ziprasidone capsules of 20,40, 60 and 80 mg in strength. Subjects will be dosed for 4 weeks using a flexible dosing design. Dosing is stratified based on weight, with subjects \<45 kg having a target dose range of 60-80 mg/day and subjects \>/= 45 kg having a target dose range of 120-180 mg/day.

Protocol document:
Prot_001.pdf: 
CP-88,059-1 A1281198
Final Protocol Amendment 2, 19 February 2019
A PHASE 3, MULTICENTER, FOUR-WEEK, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP EFFICACY AND SAFETY TRIAL OF FLEXIBLE DOSES OF 
ORAL ZIPRASIDONE IN CHILDREN AND ADOLESCENTS WITH BIPOLAR I 
DISORDER (CURRENT OR MOST RECENT EPISODE MANIC)
Compound:
CP-88,059-1
Compound Name (if applicable):
Ziprasidone Hydrochloride
United States (US) Investigational New 
Drug (IND) Number (if applicable):
European Clinical Trial Database 
(EudraCT) Number (if applicable):
N/A
Protocol Number:
A1281198
Phase:
3
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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CP-88,059-1 A1281198
Final Protocol Amendment 2, 19 February 2019
Document History
Document
Version Date
Summary of Changes
Original protocol
08 October 2013
N/A
Amendment 1
7 August 2018
For this amendment there is one 
substantial change and several 
non-substantial changes noted 
below: 
Substantial:
The requirement that female 
subjects have two pregnancy tests 
separated by a 2 week period before 
they can be randomized to study 
drug has posed significant 
challenges to investigators due to 
the fact that these subjects are in a 
current manic state and treatment of 
their mania is being delayed.  In 
several cases, investigators have 
withdrawn female subjects during 
the screening period so they could 
be more rapidly medicated for 
treatment of their manic symptoms.
We are proposing instead to obtain 
pregnancy tests in all female 
subjects at all study visits and 
believe this approach should provide 
adequate surveillance of female 
subjects for pregnancy while 
avoiding further delaying the 
treatment of their manic symptoms.
Pregnancy testing will be done 
weekly with no 14 day screening 
window. Weekly and follow-up 
laboratory testing for such testing 
has been addressed within sections 
below.
Section 3. STUDY DESIGN, 
paragraphs 4, 6 and 7.
Section 6.2. Visit 2 (Day 1) -
Baseline, paragraph 1 and bullet 6.
Section 6.3.1. Visit 3 (Day8/Week 


CP-88,059-1 A1281198
Final Protocol Amendment 2, 19 February 2019
1) bullet 3.
Section 6.3.2. Visit 4 (Day 15/end 
of Week 2) bullet 3.
Section 6.3.3 Visit 5 (Day 22/end of 
Week 3) bullet 3.
Section 6.4. Visit 6 (Day 29/end of 
Week 4) - End of Treatment (or 
Early Termination), last paragraph.
Section 6.5. Visit 7, Follow-up Visit 
(Day 36/end of Week 5), paragraphs 
1,3 bullet 4.
Section 7.1 Pregnancy Testing.
Section 7.2.1. Laboratory 
Assessments paragraph 3, last 
bullet. 
Non-substantial: 
This protocol amendment details the 
addition of an open-label extension 
study, removal of the SBQR scale 
and clarity on inclusion criteria. 
The CSSR-S is performed at 
Screening, Baseline and every 
post-baseline visit. Including the 
SBQ-R at screening is redundant 
and has not provided any additional 
benefit in detection of suicidal 
ideation/behavior over and beyond 
the CSSR-S. Removal of the 
SBQ-R rating also reduces the 
assessment burden to patients.
In addition clerical and grammar 
updates have been addressed and 
new approved template language 
was applied to this amendment.
1)Open Label Study sections noted 
below:
Schedule of Activities.
PROTOCOL SUMMARY, Study 
Design, LAST 2 PARAGRAPHS.
Section 3.1. Post Study Care 


CP-88,059-1 A1281198
Final Protocol Amendment 2, 19 February 2019
Program, paragraphs 2, 3 and 5.
Section 5.3.3.6. Dose Reductions.
Section 7.2.6. 12-lead 
Electrocardiogram (ECG), last 
sentence.
2) Removal of SBRQ scale and 
updated language to inclusion and 
exclusion criteria.
Section 4.1. Inclusion Criteria.
Section 4.2. Exclusion Criteria, 
bullet 3 and criteria 40.
Section 7.2.9.1. Suicidality 
Assessments at Screening, bullet 3.
7.2.9.4. Suicidal Behaviors 
Questionnaire-Revised (SBQ-R) on 
inclusion criteria.
3) New protocol template language 
was addressed in sections noted 
below:
Section 4.4. Life Style Guidelines.
Section 5.3.3.7. Medication Errors.
Section 8.1. Adverse Events.
Section 8.2. Reporting Period.
Section 8.3. Definition of an 
Adverse Event bullet 13.
Section 8.4. Medication Errors.
Section 8.6.2. Potential Cases of 
Drug-Induced Liver Injury.
Section 8.7. Hospitalization.
Section 8.10. Exposure During 
Pregnancy.
Section 8.11. Occupational 
Exposure.
Section 8.12. Withdrawal Due to 
Adverse Events (See Also Section 
6.7 Subject Withdrawal).
Section 8.14.1. Serious Adverse 
Event Reporting Requirements, 




CP-88,059-1 A1281198
Final Protocol Amendment 2, 19 February 2019
Language was applied to reflect the 
FDA agreed upon increase in 
sample size due to the rater training 
issue and adding a separate 
Sensitivity Analysis of Final Data 
Set. The study analysis section was 
updated to reflect the new power 
applied to the study. Language was 
added to speak to country specific 
rater training qualifications. 
Summary, Study Design, paragraphs 
3-5.
Summary, Statistical Methods, 
paragraphs 1, 3-5.
Section 3. Study Design, paragraph 
3, sentence 1.
Section 6.1. Screening, paragraphs 
3, 4.
Section 9.1. Sample Size 
Determination, paragraphs 3, 5-6.
Non substantial: 
Language added for country specific 
guidance on alternative treatment. 
Language added for country specific 
guidance on alternative treatment.
In addition, clerical and grammar 
updates have been addressed and 
new approved template language 
was applied to this amendment.  
Summary, Study Treatments, 
paragraph 6, sentence 1.
Schedule of Activities
Section 3. Study Design, paragraph 
3, sentence 1 Section 3. Study 
Design, Schema.
Section 3.1 Post Study Care 
Program, paragraphs 2-3, and 6.
Section 4.2 Exclusion Criteria, 
bullet 1, numbers 8, 22, 38, 39 and 
40.
Section 5.5. Concomitant 


CP-88,059-1 A1281198
Final Protocol Amendment 2, 19 February 2019
Medication (s), Table, row 3.
Section 6.3.2. Visit 4 (Day 15/end 
of Week 2), bullet 3.
Section 6.5. Visit 7, Follow up Visit 
(Day 36/end of Week 5), paragraphs 
1 and 3.
7.2.9.3 Columbia Suicide Severity 
Rating Scale (C-SSRS).
Section 8.2. Reporting Period.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).




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STUDY DESIGN
This will be a Phase 3, multicenter, 4-week, randomized, double-blind, placebo-controlled, 
parallel-group trial to evaluate the efficacy, safety, and tolerability of flexibly dosed 
ziprasidone compared with placebo for the treatment of Bipolar I Disorder (current or most 
recent episode manic) in children and adolescents aged 10 to 17 years (inclusive).
Ziprasidone (or placebo) will be administered as oral capsules given twice daily (BID) with 
food.  Ziprasidone (or placebo) will be titrated over the first 7-14 days of treatment, and then 
flexibly dosed through the end of the double-blind treatment period (Week 4, Day 29).
Sample Size 
Shortly after enrollment into this study commenced, Pfizer was informed by the rater training 
vendor (on 29 September 2014) that an internal audit had revealed an error in their internal 
processes. This error resulted in some sites being notified that they could start screening 
subjects before all raters at the sites had completed all of the required rater training activities. 
The primary endpoint assessments (YMRS) and/or the diagnostic interviews (KSADS) of 
14 subjects were impacted by the rater training issue.
In agreement with the FDA to ensure the robustness of the inferential analysis, Pfizer will 
recruit an additional 14 subjects into the study and conduct a sensitivity analysis excluding 
these 14 subjects to mitigate the effect of the rater training issue that was identified.
The original sample size for this study was 180 subjects.  For the revised sample size, a total 
of 194 subjects (97 ziprasidone: 97 placebo) will be recruited from approximately 60 -70 
worldwide sites.  The power of the study including the additional subjects is 88%. It is 
estimated that approximately 300 subjects will be required to be screened to achieve this 
enrollment target with an anticipated screen failure rate of approximately 40%.
The study will begin with a screening visit to determine subject eligibility, followed by a 
1-14 day period to allow for wash-out of exclusionary medications.  Subjects who qualify 
will be randomized at baseline to receive either double-blind oral ziprasidone or placebo
(randomization ratio 1:1).
Eligible subjects will remain in the treatment period for 4 weeks.  After completion of the
treatment phase, subjects will return for a post-treatment follow-up visit at week 5.  Subjects 
who complete the study or who terminate early may be eligible for continuation of treatment 
in the open label extension study A1281201.
Subjects with a body weight 45 kg who cannot tolerate a dose of 80 mg/day and subjects 
weighing <45 kg who cannot tolerate a minimum dose of 40 mg/day will discontinue from 
the double blind study and will not be eligible for continuation of treatment in the open-label 
extension study. These subjects will be eligible for the Post Study Care program (see 
Section 3.1).


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STUDY TREATMENTS
Study drug will be provided by Pfizer and will include oral ziprasidone capsules of 20 mg, 
40 mg, 60 mg, and 80 mg strength and matching placebo capsules.  All medication will be 
packaged in child resistant blister cards with columns for AM and PM capsules.
Study medication will be dispensed at the baseline visit after all baseline assessments have 
been completed.  A single titration card will be dispensed based on the subject’s weight 
(45 kg or <45 kg) for the first week of dosing. The titration cards that will be used for the 
first week of the trial will have a maximum of 80 mg/day for subjects 45 kg and a 
maximum of 60 mg/day for subjects <45 kg.  Subsequent dosing will follow as per the 
parameters of Section 5 of the protocol. Dosing flexibility is allowed based on the clinical 
judgment of the investigator regarding tolerability and efficacy of the subject.
In general, the target dose should be attained by Days 7-14.  For subjects with a body 
weight ≥45 kg, the target dose range is 120-160 mg/day.  A dose of 160 mg/day should not 
be achieved before Day 14 of treatment, however. For subjects with a body weight 
<45 kg, the target dose range is 60-80 mg/day.  A dose of 80 mg/day should not be achieved 
before Day 8 of treatment.
After subjects have been titrated to the target dose range, double-blind dosing will continue 
to the end of Week 4, during which time the dose should be kept stable except that downward 
adjustments of the dose are allowed if required in the judgment of the investigator for safety 
and tolerability concerns.
All study medication is to be taken with food.
At the end of the double-blind treatment period, subjects may be switched to one of the 
alternative therapies for treatment of pediatric bipolar disorder approved within their country 
for the U.S. (including lithium, Abilify®, Risperdal®, Zyprexa®, and Seroquel®) if in the 
judgment of the investigator or treating physician, continued pharmacotherapy is warranted.  
Based on accumulated safety data from the pre-marketing clinical trials with ziprasidone, 
short term treatment with ziprasidone does not appear to be associated with a marked 
withdrawal syndrome and it should be feasible and well tolerated to immediately switch the 
subjects from ziprasidone treatment to an alternative treatment. Following the last dose of 
study drug, ziprasidone plasma concentrations should self-taper over 2 to 3 days, during 
which time the alternative medication can be titrated up to ensure that treatment of the 
subject is not interrupted.
STATISTICAL METHODS
This study has been designed to have 85% statistical power to show a difference between 
drug and placebo at conventional levels (ie, 5% level, 2-sided) of statistical significance.  
Based on the previous Pfizer pediatric study A1281132, the estimated difference in change 
from baseline of the YMRS total score for ziprasidone versus placebo is –4.55 points (from 
descriptive and LSMEANs at week 4) with an approximate within-group standard deviation 
of 8.0.  Using EAST (version 5.4) for a two-sample t-test, the sample size needed to detect 


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this difference with 85% power at a two-sided significance level of 5% was determined to be 
111 randomized subjects.  Adjusting for dropouts (approximately 38% at week 4) and 
including the additional 14 subjects being enrolled to mitigate the impact of the rater training 
issue, the total sample necessary is 194 subjects (1:1 enrollment with 97 on ziprasidone and 
97 on placebo). The power for this study has now increased to 88%. The randomization will
be stratified by weight group (weight <45 kg, weight ≥45 kg) to ensure treatment balance 
within each of the two weight groups.
Both the Intent-to-Treat (ITT) and Per-Protocol (PP) analysis sets will be used in the analyses 
of all efficacy endpoints, with the ITT being primary. The Safety Analysis Set will be used 
in the analyses of the safety data. Only the ITT analysis set will be used in the analyses of 
the outcome and special safety assessments.
Sensitivity Analysis of Final Data Set
The YMRS data of 14 subjects was impacted by the rating training issue, representing about 
7% of the target sample size of 194 subjects. While we remain confident of the validity of 
these data, we plan to conduct a sensitivity analysis of the treatment effect on the primary 
endpoint, excluding these 14 subjects from the analysis.  The power for this sensitivity 
analysis is 85%, to detect a difference in means of -4.5, with a standard deviation of 8, and 
assuming a dropout at week 4 of 38%.
The sensitivity analysis excluding these 14 patients will use the same statistical methodology 
as the pre-specified primary efficacy analysis. 








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TABLE OF CONTENTS
PROTOCOL SUMMARY.........................................................................................................8
SCHEDULE OF ACTIVITIES................................................................................................12
LIST OF TABLES...................................................................................................................19
APPENDICES .........................................................................................................................19
1. INTRODUCTION ...............................................................................................................20
1.1. Indication.................................................................................................................20
1.2. Background and Rationale ......................................................................................20
1.2.1. Background on Bipolar I Disorder in Children and Adolescents...............20
1.2.2. Background on Ziprasidone (CP-88,059)...................................................21
1.2.2.1. Background on Previous Ziprasidone Pediatric Trials..............22
1.3. Drug Development/Study Rationale .......................................................................26
1.4. Dose Rationale ........................................................................................................26
1.5. Risk-Benefit Assessment.........................................................................................26
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................27
2.1. Objectives................................................................................................................27
2.1.1. Primary Objectives .....................................................................................27
2.1.2. Secondary Objectives .................................................................................27
2.2. Endpoints.................................................................................................................28
2.2.1. Primary Endpoints ......................................................................................28
2.2.2. Secondary Endpoints ..................................................................................28
2.2.4. Safety Endpoints.........................................................................................28
3. STUDY DESIGN.................................................................................................................29
3.1. Post Study Care Program ........................................................................................30
4. SUBJECT SELECTION......................................................................................................31
4.1. Inclusion Criteria.....................................................................................................31
4.2. Exclusion Criteria....................................................................................................33
4.3. Randomization Criteria ...........................................................................................36
4.4. Life Style Guidelines...............................................................................................36
4.5. Sponsor Qualified Medical Personnel.....................................................................37
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5. STUDY TREATMENTS.....................................................................................................38
5.1. Allocation to Treatment ..........................................................................................38
5.2. Breaking the Blind ..................................................................................................38
5.3. Drug Supplies..........................................................................................................38
5.3.1. Formulation and Packaging........................................................................38
5.3.2. Preparation and Dispensing........................................................................39
5.3.3. Administration............................................................................................44
5.3.3.1. Baseline (Day 1)/Visit 2............................................................44
5.3.3.2. Day 8/Visit 3 (end of Week 1) ..................................................45
5.3.3.3. Day 15/Visit 4 (end of Week 2) ................................................45
5.3.3.4. Day 22/Visit 5 (end of Week 3) ................................................45
5.3.3.5. Day 29/Visit 6 (end of Week 4) ................................................46
5.3.3.6. Dose Reductions........................................................................46
5.3.4. Compliance.................................................................................................46
5.4. Drug Storage and Drug Accountability...................................................................47
5.5. Concomitant Medication(s).....................................................................................47
6. STUDY PROCEDURES .....................................................................................................50
6.1. Screening.................................................................................................................50
6.1.1. Screen Fail Subject .....................................................................................52
6.2. Visit 2 (Day 1) - Baseline........................................................................................52
6.3. Treatment Period.....................................................................................................53
6.3.1. Visit 3 (Day 8/Week 1)...............................................................................53
6.3.2. Visit 4 (Day 15/end of Week 2)..................................................................54
6.3.3. Visit 5 (Day 22/end of Week 3)..................................................................55
6.4. Visit 6 (Day 29/end of Week 4) - End of Treatment (or Early Termination) .........55
6.5. Visit 7, Follow-up Visit (Day 36/end of Week 5)...................................................57
6.6. Unscheduled Visits..................................................................................................58
6.7. Subject Withdrawal.................................................................................................58
6.7.1. Specific Withdrawal Criteria......................................................................59
7. ASSESSMENTS..................................................................................................................60
7.1. Pregnancy Testing...................................................................................................61
7.2. Safety Assessments .................................................................................................61


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7.2.1. Laboratory Assessments.............................................................................61
7.2.1.1. Total Volume of Blood Collected .............................................64
7.2.2. Urine Drug Screen ......................................................................................64
7.2.3. Full Physical Examination..........................................................................65
7.2.4. Body Weight, Height, BMI, BMI z-score, and Waist Circumference .......65
7.2.5. Blood Pressure/Pulse (Sitting and Standing)..............................................65
7.2.6. 12-lead Electrocardiogram (ECG)..............................................................66
7.2.7. Child Depression Rating Scale – Revised (CDRS-R)................................66
7.2.8. Movement Disorder Scales.........................................................................67
7.2.8.1. Simpson-Angus Rating Scale (SARS)......................................67
7.2.8.2. Barnes Akathisia Rating Scale (BAS).......................................67
7.2.8.3. Abnormal Involuntary Movement Scale (AIMS) .....................68
7.2.9. Suicidality Assessments..............................................................................68
7.2.9.1. Suicidality Assessments at Screening .......................................68
7.2.9.2. Suicidality Assessments at Baseline and Post-baseline 
Visits..................................................................................................68
7.2.9.3. Columbia-Suicide Severity Rating Scale (C-SSRS).................69
7.2.10. Subject Contact.........................................................................................70
7.3. Efficacy Assessments..............................................................................................70
7.3.1. Young Mania Rating Scale (YMRS)..........................................................70
7.3.2. Clinical Global Impression Scales (CGI-S and CGI-I) ..............................70
7.4. Rater Qualifications/Training/Certification for Diagnostic, Efficacy, and 
Safety Rating Scales..................................................................................................71
7.6. Triggered Requirements..........................................................................................74
8. ADVERSE EVENT REPORTING......................................................................................75
8.1. Adverse Events........................................................................................................75
8.2. Reporting Period .....................................................................................................75
8.3. Definition of an Adverse Event...............................................................................76
8.4. Medication Errors....................................................................................................77
8.5. Abnormal Test Findings..........................................................................................77
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8.6. Serious Adverse Events...........................................................................................77
8.6.1. Protocol-Specified Serious Adverse Events...............................................78
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................78
8.7. Hospitalization ........................................................................................................79
8.8. Severity Assessment................................................................................................80
8.9. Causality Assessment..............................................................................................81
8.10. Exposure During Pregnancy..................................................................................81
8.11. Occupational Exposure .........................................................................................82
8.12. Withdrawal Due to Adverse Events (See Also Section 6.7. Subject 
Withdrawal)...............................................................................................................82
8.13. Eliciting Adverse Event Information ....................................................................83
8.14. Reporting Requirements........................................................................................83
8.14.1. Serious Adverse Event Reporting Requirements .....................................83
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................83
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................84
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................84
9.1. Sample Size Determination.....................................................................................84
9.2. Statistical Summary and Analysis...........................................................................85
9.3. Definition of Study Populations..............................................................................85
9.4. Study Conduct and Subject Disposition..................................................................85
9.5. Baseline Characteristics and Treatment Group Comparability...............................85
9.6. Efficacy Analysis ....................................................................................................85
9.6.1. Analysis of Primary Endpoint ....................................................................86
9.6.2. Analysis of Secondary Endpoints...............................................................86
9.8. Analysis of Safety Assessments..............................................................................87
9.9. Analysis of Special Safety Assessments .................................................................89
9.11. Interim Analysis ....................................................................................................90
9.12. Data Monitoring Committee .................................................................................90
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................90
11. DATA HANDLING AND RECORD KEEPING .............................................................91
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11.1. Case Report Forms/Electronic Data Record .........................................................91
11.2. Record Retention...................................................................................................91
12. ETHICS..............................................................................................................................92
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............92
12.2. Ethical Conduct of the Study ................................................................................92
12.3. Subject Information and Consent..........................................................................92
12.4. Subject Recruitment ..............................................................................................94
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................94
13. DEFINITION OF END OF TRIAL...................................................................................94
13.1. End of Trial in all Participating Countries ............................................................94
14. SPONSOR DISCONTINUATION CRITERIA ................................................................95
15. PUBLICATION OF STUDY RESULTS..........................................................................95
15.1. Communication of Results by Pfizer ....................................................................95
15.2. Publications by Investigators ................................................................................96
16. REFERENCES ..................................................................................................................97
LIST OF TABLES
Table 1.
45 kg Titration Regimen for Day 1/Visit 2 ........................................................40
Table 2.
<45 kg Titration Regimen for Day 1/Visit 2 ........................................................40
Table 3.
45 kg Titration Regimen for Day 8/Visit 3 ........................................................41
Table 4.
100 mg Fixed Dose Regimen ...............................................................................41
Table 5.
80 mg Fixed Dose Regimen .................................................................................42
Table 6.
160 mg Fixed Dose Regimen ...............................................................................42
Table 7.
60 mg Fixed Dose Regimen .................................................................................43
Table 8.
40 mg Fixed Dose Regimen .................................................................................43
APPENDICES
Appendix 1. Abbreviations....................................................................................................100


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1. INTRODUCTION
The present study is designed to assess the efficacy, safety, and tolerability of oral 
ziprasidone in child and adolescent subjects with Bipolar I Disorder (current or most recent 
episode manic).  It is designed to comply with a Pediatric Research Equity Act (PREA) 
commitment to assess the safety and effectiveness of Geodon® (ziprasidone) as a treatment 
for bipolar disorder in pediatric patients ages 10 to 17 (children and adolescents), issued by 
the US Food and Drug Administration (FDA) to Pfizer in August 2004. 
1.1. Indication
Ziprasidone is an atypical antipsychotic with a high affinity for the dopamine D2 receptor and 
the 5-HT2A receptors.  It blocks re-uptake of serotonin and norepinephrine and exhibits 
5-HT1A agonist activity.  The indication for this study is pediatric Bipolar I Disorder. The 
study will include in-patient and/or out-patient male and female subjects 
aged 10-17 (inclusive) who meet the DSM-V diagnostic criteria for Bipolar I Disorder
(current or most recent episode manic).
1.2. Background and Rationale
1.2.1. Background on Bipolar I Disorder in Children and Adolescents
Bipolar I Disorder is a lifelong disease that is potentially debilitating to the patient and 
presents serious complications within the patient’s family structure. Over half of all bipolar 
patients report that their symptoms first emerged during childhood or adolescence, and onset 
before adulthood is associated with greater social morbidity.1 Children and adolescents with 
mania often show markedly labile mood, with a mixed or dysphoric picture and intense 
irritability, as well as severe psychosocial impairment.2,3  The costs to society and the public 
health system are immense. Recognizing the onset of these disorders in children or 
adolescents is a critical health concern, and initiating treatment as early as possible is vital to 
maximize the probability of a positive outcome for the patient.
Bipolar disorder can be reliably diagnosed in children and adolescents aged 10-17 years, 
using the same criteria used for adults as outlined in the Diagnostic and Statistical Manual of 
Mental Disorders - Fifth Edition (DSM-V), and supported by structured diagnostic interviews 
such as the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), as 
affirmed recently by the American Academy of Child and Adolescent Psychiatry (AACAP) 
guidelines.4  Existing data support the diagnostic and therapeutic continuity between adult 
and pediatric bipolar disorder. For adults with acute mania in the setting of bipolar disorder, 
the efficacy and safety of a variety of medications has been established through randomized 
clinical trials. These agents include lithium, other mood stabilizers from the anticonvulsant 
class, and atypical antipsychotic medications.  For children with bipolar mania, however, 
there are limited data on the safety and efficacy of these pharmacological agents.6  Lithium 
and other mood stabilizers are commonly used for this diagnosis, but the evidence base is not 
robust for any of these drugs, and except for lithium (for children 12 and older), none of the 
other mood stabilizers are FDA-approved for this indication.4,6  Among the class of atypical 
antipsychotic medications, risperidone (Risperdal®), aripiprazole (Abilify®), and more 
recently, quetiapine (Seroquel®) and olanzapine (Zyprexa®) have been approved for the 
treatment of pediatric bipolar mania.  Although shown to be effective, several of these 


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treatments are associated with adverse events such as movement disorders, weight gain, 
hyperlipidemia and other metabolic effects, which may limit their usefulness in some 
patients.7  There remains a great need for additional well-controlled, randomized, 
double-blind clinical studies to evaluate the efficacy and safety of potential 
pharmacotherapies in the pediatric population.
1.2.2. Background on Ziprasidone (CP-88,059)
Ziprasidone (CP-88,059-1 oral capsule) is an atypical antipsychotic. It has a high affinity for 
the dopamine D2 receptor, potent in vivo activity in rat models of dopamine antagonism 
(blocking of d-amphetamine-induced locomotor activation and blocking of 
apomorphine-induced stereotypy), and potent activity in an antipsychotic model in rats that is 
potentially dopamine-independent (inhibition of conditioned avoidance). Ziprasidone 
demonstrates high 5-Hydroxytryptamine Receptor 2A (5-HT2A/)D2 ratio, which has been 
associated with a lower risk of extrapyramidal symptoms compared to typical antipsychotics.  
In addition, blockade of serotonin and norepinephrine re-uptake and 
5-Hydroxytryptamine Receptor 1A (5HT1A) agonist activity may contribute to the alleviation 
of affective and negative symptoms.  Ziprasidone has relatively low affinity for 
α1-adrenergic and histamine H1 receptors and muscarinic M1 receptors, which may be 
associated with modest orthostatic effects and sedation, and low incidence for weight gain 
and anticholinergic side effects, respectively.8  Because ziprasidone is metabolized 
predominantly by the aldehyde oxidase system, in addition to the cytochrome 
P4503A4 (CYP3A4) system, the likelihood of pharmacokinetic interactions between 
ziprasidone and other drugs is low.9
Ziprasidone has been approved by the Food and Drug Administration (FDA) for the 
treatment of schizophrenia in adults in the United States (approval, February 2001) and in at 
least 55 other countries.  A Supplemental New Drug Application (sNDA) for the treatment of 
bipolar disorder in adults with manic symptoms was approved by the FDA in August 2004. 
The safety and efficacy of ziprasidone monotherapy for the treatment of mania in adults was 
demonstrated in two double-blind, placebo-controlled trials of 3 weeks duration, and in 
open-label extension trials of up to 104 weeks duration. These studies demonstrated that 
ziprasidone was superior to placebo in the treatment of subjects with a manic or mixed 
bipolar episode, with clinically and statistically significant improvement evident as early as 
Day 2 of treatment. In November 2009, ziprasidone was also approved by the FDA for adult 
bipolar maintenance treatment based on a 6 month double-blind study comparing ziprasidone 
plus a mood stabilizer vs placebo plus a mood stabilizer in subjects who have been treated 
and responded for at least 4 months to open-label treatment with both agents. The overall 
profile of adverse events in the adult mania studies is comparable with that seen in 
schizophrenia studies.  Ziprasidone had neutral effects on weight, glucose and lipid profiles 
in adult patients with mania.8
Currently approved and marketed formulations in the US for ziprasidone include the oral 
capsule (20, 40, 60, and 80 mg) and a rapid onset intramuscular (IM) injectable form 
(20 mg/ml).  As of October 2017, approximately 2,976,798 patients had been exposed to 
ziprasidone worldwide, cumulatively (based on prescription data and US unique patient 
count).


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Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Brochure.10
1.2.2.1. Background on Previous Ziprasidone Pediatric Trials
1.2.2.1.1. Study A1281123: Open Label Safety & Tolerability
Study A1281123 was an open-label safety and tolerability study in children and adolescents 
10-17 years old, diagnosed with Bipolar I (manic or mixed), schizophrenia or schizoaffective 
disorder.  This Phase 2 study explored the range of tolerated doses of ziprasidone during 
3-weeks of low or high fixed dose administration, and characterized the safety and 
tolerability of flexibly dosed ziprasidone for an additional 24 weeks.  Ziprasidone oral 
suspension was titrated over 10 days to a target dose following a fixed schedule, and then 
maintained at the target dose until end of Week 3 (Period 1).  Two dose ranges were tested: 
Group 1 subjects (low dose, n=23) started from 10 mg BID to a target dose of 40 mg BID, 
and Group 2 subjects (high dose, n=40) started from 20 mg BID to a target dose of 80 mg 
BID.  Doses for subjects weighing <45 kg were halved. Subjects could continue flexible 
dosing in a range of 10-80 mg BID into Period 2 for up to 24 additional weeks. The most 
common AEs in Groups 1 and 2 were sedation (21.7%, 35.0%), somnolence (34.8%, 27.5%), 
nausea (21.7%, 27.5%), headache (13.0%, 27.5%), dizziness (13.0%, 25.0%), and vomiting 
(13.0%, 20%). No unexpected safety or tolerability findings occurred. ECG findings were 
consistent with those recorded for adult subjects treated with ziprasidone. There were no 
confirmed QTc intervals over 500 msec and no subject had a QTc increase 60 msec from 
baseline. Most subjects (89%) continued treatment in the 6-month open-label flexible dose 
extension; and 31 (55%) completed the 6-month treatment. Only sedation (30.4%) and 
somnolence (30.4%) occurred in more than 20% of the subjects.  Weight gain was reported 
as an adverse event (AE) in 5 of 56 subjects (8.9%).  No clinically relevant changes in lipid 
profile or fasting glucose were observed. Twenty SAEs were reported in 16 subjects.  One 
event (QTc prolongation) was initially reported as related to treatment; this event occurred 
after termination of therapy, and the causality was subsequently changed to not related to 
study drug.  All other events were unrelated to treatment. Five cases of suicidal ideation and 
one of self-harm (overdose) were explained by the underlying disorder, pre-existing suicidal 
ideation, and situational stressors.  The higher AE rate in Group 2 (high dose group) in the 
A1281123 study was attributed partly to the relatively high initial dosing (20 mg BID) and
partly to the relatively fast, fixed titration to 80 mg BID, which may not have been tolerated 
well by some subjects. On the basis of these results, a lower starting dose and a slower, 
flexible dose titration schedule with lower target dose range were identified for the 
placebo-controlled Phase 3 studies in pediatric subjects.
1.2.2.1.2. Study A1281132 and Extension Study A1281133: Pediatric Bipolar I Disorder
Study A1281132 was a Phase 3, 4-week, double-blind, placebo-controlled trial to evaluate 
the safety and efficacy of flexibly dosed ziprasidone in the treatment of pediatric subjects 
(ages 10-17 years, inclusive) diagnosed with Bipolar I Disorder, manic or mixed episode, as 
defined by DSM-IV criteria and confirmed by the K-SADS semi-structured diagnostic 
interview.  The inclusion criteria required that subjects have an YMRS score of 17 or greater 
at screening and baseline. Ziprasidone (oral capsule) was administered twice daily (BID) 
with meals, titrated over the first 1-2 weeks of treatment and flexibly dosed during 


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Weeks 3 and 4.  Ziprasidone was titrated from a starting dose of 20 mg/day with dose 
increases of 20 mg/day every 1 or 2 days up to a target dose of 120-160 mg/day for subjects 
weighing 45 kg. The target dose was to be obtained by Day 14. The dose was to increase 
above 120 mg/day only in subjects who tolerated 120 mg/day. For children weighing 
<45 kg, the target dose was 60-80 mg/day and a more gradual dose escalation was employed.  
A total of 149 subjects received ziprasidone and 88 subjects received placebo in a 
2:1 randomization, with 65% in the ziprasidone group and 58% in the placebo group 
completing the study.  The mean age of the subjects was 13.6 years in the ziprasidone group 
and 13.7 years in the placebo group.  In this trial, ziprasidone was demonstrated to be 
superior to placebo based on primary efficacy endpoint (change from baseline to 
Week 4 YMRS total score), as well as the key secondary assessment (the change from 
baseline in CGI-S score at Week 4) and the secondary assessment endpoint (the change from 
baseline in CGI-I score at Week 4).  For the exploratory outcome assessments, there was 
evidence from the Children’s Global Assessment Scale (CGAS) that ziprasidone-treated 
subjects had improved scores compared to placebo and those subjects who were reported to 
be in school had better responses to ziprasidone treatment.  Based on the Neurocognitive 
Index score of the central nervous system (CNS) Vital Signs Cognitive Battery, there was no 
change in cognition with treatment.  Overall, ziprasidone was safe and generally well 
tolerated.  No new or unexpected AEs were observed in the study.  In the ziprasidone group, 
commonly occurring AEs were attributed to the known pharmacologic effects of ziprasidone 
in adults.  The most common all causality AEs in the ziprasidone group were sedation 
(32.9%), somnolence (24.8%), headache (22.1%), fatigue (15.4%), nausea (13.4%) and 
dizziness (12.8%).  A total of 13 subjects (6 from the ziprasidone group and 7 from the 
placebo group) reported 19 SAEs.  One subject in the ziprasidone group was administered an 
overdose of ziprasidone and had an acute dystonic reaction due to the study treatment; the 
subject was discontinued from the study and recovered without sequelae.  All other SAEs 
were attributed to either disease under study or other illnesses.  Ziprasidone was not 
associated with any change in weight or metabolic parameters in this 4-week study; one 
subject each in the ziprasidone and placebo group reported AE of weight gain.  There were 
no new or unexpected safety findings in vital signs, or ECGs.  No subject had a QT interval, 
Bazett’s correction (QTcB), or QTcF that was 500 msec or higher.  One subject in the 
ziprasidone group (60 mg) had an AE of prolonged (greater than 460 msec) QTcF that 
resulted in discontinuation.  There were no suicides or increase in suicidality during this 
study.
The A1281133 study was a 26 week open-label extension Phase 3 study, evaluating the 
safety and tolerability of oral ziprasidone in children and adolescents diagnosed with Bipolar 
I Disorder, manic or mixed episode.  Subjects who participated in Study A1281132, and who 
met qualification criteria for this study, were allowed to participate in the open-label 
extension with flexible dose active ziprasidone.  Subjects were tapered off their study 
treatment (double-blind active or placebo, with identical treatment assignment as in the 
preceding double-blind trial) during the first 6 days and then ziprasidone was titrated up over 
2 weeks, in a similar way as in the double-blind study (A1281132).  After the Week 2 visit, 
dosing was flexible, with dosing adjustments made at the discretion of the investigator to 
maintain optimal efficacy and tolerability.  The target dose range was 40-80 mg BID 
(80-160 mg/day total dose) for subjects weighing ≥45 kg, and 20-40 mg BID (40-80 mg/day 


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total dose) for those weighing <45 kg.  A total of 162 subjects received study treatment, and 
67 subjects (41%) completed the study.  While no formal efficacy analyses were performed 
in this study, both efficacy assessments (YMRS and CGI-S scores) showed trends of 
improved scores with continued ziprasidone treatment.  Overall, ziprasidone was safe and 
generally well tolerated following 26 weeks of continued administration. No new or 
unexpected AEs were observed in this pediatric population as compared to adult studies with 
ziprasidone.  Commonly occurring AEs were attributed to the known pharmacologic effects 
of ziprasidone in adults.  Most common AEs (all causality) were sedation (26.5%), 
somnolence (23.5%), headache (22.2%) and insomnia (13.6%). Nineteen subjects had 1 or 
more treatment-emergent SAEs. Only 2 of these subjects had treatment-related SAEs 
(aggravated sedation and constipation) that led to discontinuation from the study; both 
subjects recovered from these events.  A total of 26 subjects discontinued the study due to
1 or more AEs that were judged to be related to the study treatment by the investigator.  
These AEs included sedation (n=9), somnolence (n=5), fatigue (n=4), aggression (n=2), and 
1 subject each reported to have insomnia, abdominal pain/duodenitis, akathisia, mania, 
exacerbation of Bipolar I disorder, prolongation of ECG, depression, rash, and restlessness.  
The changes in BMI derived Z-scores, which adjust for age and sex, showed little or no 
change throughout the study.  There were no notable changes in metabolic parameters. There 
were no new or unexpected safety findings in laboratory tests, vital signs, or ECGs.  No 
subject had a QT interval, QTcB, or QTcF that was 460 msec or higher.
One subject receiving 80 mg total daily dose of ziprasidone had an AE of prolonged QTc 
interval (66 msec prolongation compared to baseline measure) and was discontinued from the 
study.  None of this subject’s QTc measures were >460 msec.  There was no increase in 
suicidal ideation or behavior, and there were no suicides during this study.
1.2.2.1.3. Study A1281134 (and Open Label Extension A1281135): Pediatric 
Schizophrenia
Pfizer conducted 2 Phase 3 studies to evaluate the effects of ziprasidone (oral capsules) in 
adolescents (age 13-17 years) diagnosed with schizophrenia.  The A1281134 study was a 
6 week, placebo-controlled double-blind trial to evaluate the efficacy and safety of flexible 
dose ziprasidone.  Eligible subjects could continue in the open-label study A1281135, to 
evaluate the safety and tolerability of flexible dose ziprasidone over 26 weeks. The 
weight-based flexible titration regimens and target doses in these two studies were the same 
as in the pediatric bipolar studies A1281132 and A1281133.  A planned interim analysis 
resulted in a recommendation from the Data Safety and Monitoring Board (DSMB) to 
terminate the A1281134 study due to futility.  Pfizer terminated both studies; as a result 
participation of 1 subject in the A1281134 study and 92 subjects in the A1281135 study was 
stopped.
In the A1281134 trial, a total of 193 subjects were treated with ziprasidone and 90 subjects 
were treated with placebo in a 2:1 randomization.  Subject overall mean age was 15.3 years 
in the ziprasidone group and 15.4 years in the placebo group, and most had a primary 
diagnosis of schizophrenia, paranoid type.  While more subjects in the ziprasidone group
completed the study (69.9% vs 57.8% in the placebo group), more subjects in the placebo 
group discontinued due to insufficient clinical response (20.0% vs 9.3% in the ziprasidone 


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group).  In this study, oral ziprasidone failed to demonstrate superiority in efficacy over 
placebo in adolescent subjects.  Overall, ziprasidone was safe and generally well-tolerated.  
The higher incidence of AEs in the ziprasidone group was primarily attributed to known, 
pharmacologic nervous system effects (ie, somnolence, extrapyramidal disorder, tremor, 
akathisia, insomnia, headache, fatigue, dizziness, nausea, vomiting).  The most commonly 
occurring AEs (all causality) in the ziprasidone group were somnolence (19.2%) and 
extrapyramidal disorders (11.4%).  While the incidence of treatment-emergent AEs (all 
causality) related to extrapyramidal symptoms was higher in the ziprasidone group (24.9% in 
ziprasidone group vs 5.6% in the placebo group), evaluation of these symptoms using the
Movement Disorder Scales did not reveal statistically significant differences between the 
treatment groups.  The incidence of SAEs in the ziprasidone group compared to placebo was 
4.7% vs 1.1%, respectively; none of the SAEs were considered treatment related.  The SAEs 
in the ziprasidone group were suicidal ideation, anxiety, depression, psychotic disorder, 
schizophrenia, auditory hallucination, hostility, impulsive behavior and overdose.  The SAEs 
in the placebo group were aggression and psychotic disorder.  Suicidality was assessed using 
the Columbia Classification system for Possibly Suicide Related Adverse Events (PSRAEs).  
Four PSRAEs in the ziprasidone group were considered SAEs (suicidal ideation and 
self-injurious behavior, intent unknown, in 2 subjects each).  Changes in BP and pulse rate 
were not clinically significant.  Two subjects had a QTcF increase of 460 msec but 
<500 msec.  Two subjects treated with ziprasidone had AEs of QTcF prolonged (1 mild and 
1 moderate) leading to discontinuations from the study.  Ziprasidone did not have clinically 
significant effects on weight and metabolic indices such as fasting glucose and lipids.
A total of 221 adolescent schizophrenia subjects treated in the A1281134 double-blind 
placebo-controlled study entered the 26 week extension study and were treated with 
open-label ziprasidone.  The study was terminated early for futility by the sponsor; out of 
145 subjects (65.6%) who discontinued the study, 92 (41.6%) were discontinued by the 
sponsor.  Overall, ziprasidone was safe and generally well tolerated over 26 weeks of 
open-label treatment.  No new or unexpected AEs were observed during the study.  The 
majority of both all-causality and treatment-related AEs were mild in severity.  All causality 
treatment-emergent AEs occurring at an incidence of 5% were somnolence (14.5%), 
headache (8.6%), tremor (6.3%), schizophrenia (5.0%).  The self-rated Tanner Adolescent 
Pubertal Staging Questionnaire ratings indicated a progression of puberty among subjects.  
From the special safety evaluations, the decrease in the CDRS-R mean scores throughout the 
study indicated overall improvement in the level of depression.  The Children’s Problem 
Behavior and Aggression Questionnaire (CPBAQ) and CNS Vital Signs scores fluctuated, 
with no obvious trends.  One death, via suicide, occurred during this study.  The causality of 
this event was judged to be related to study medication (poor control of symptoms of 
schizophrenia).  Five other subjects (2.3%) discontinued due to AEs related to the study drug 
(sedation, somnolence, weight increased, weight decreased, and muscle rigidity) and 
1 subject discontinued due to a laboratory abnormality not related to study drug (hepatitis B, 
causality due to other illness).  Only 6 subjects (2.7%) discontinued due to insufficient 
clinical response.  Changes in blood pressure and pulse were small and not clinically 
significant.  One subject had a QTcF interval of 460 msec but <500 msec.  No subject had 
an AE of QTc prolonged.  There were no clinically significant changes in body weight, and 
other metabolic indices such as fasting glucose and lipids results. 






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2.2. Endpoints
2.2.1. Primary Endpoints
The primary endpoint of the study is the change from baseline to Week 4 in the YMRS total 
score.
2.2.2. Secondary Endpoints
The key secondary endpoint of the study is the change from baseline to Week 4 in the CGI-S
score.
Other secondary endpoints include the:
•
Change from baseline to Weeks 1, 2, and 3 in the YMRS total score;
•
Change from baseline to Weeks 1, 2 and 3 in the CGI-S score;
•
CGI-I scores at Weeks 1, 2, 3, and 4.
2.2.4. Safety Endpoints
Safety and tolerability endpoints will be assessed at scheduled intervals during the study by:
•
Adverse event monitoring;
•
Suicidality assessment monitoring via the Columbia-Suicide Severity Rating Scale 
(C-SSRS);
•
Concomitant treatment monitoring;
•
Clinical laboratory monitoring;
•
Physical Examinations;
•
Blood Pressure and Pulse;
•
Height, weight, BMI, BMI z-score, and waist circumference;
•
12-lead ECG;
•
Child Depression Rating Scale - Revised (CDRS-R) monitoring;
•
Movement disorder scale (SARS, BAS, and AIMS) monitoring.
CCI




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The end of the study will be the last visit of the last subject for purposes of closing out sites, 
informing the institutional review board/independent ethics committee (IRB/IEC), and 
stopping sending Council for International Organizations of Medical Sciences (CIOMS) 
reports.
3.1. Post Study Care Program
Treatment of Bipolar I Disorder, in both youth and adults, involves stabilization of patients’ 
acute manic symptoms and ongoing or maintenance treatment to prevent relapse.11  The
A1281198 study is a treatment study of youth in the midst of an uncontrolled bipolar I acute 
manic episode.  It is designed to confirm the efficacy of ziprasidone in the treatment and 
stabilization of acute manic symptoms in youth aged 10-17 years of age. 
The purpose of the post study care program is to ensure that medications that are approved 
for the acute treatment and stabilization of manic symptoms in pediatric subjects will be 
available to all subjects completing or early terminating from the A1281198 study who are 
ineligible for or choose not to enter the open- label extension study A1281201.  The post 
study care program will provide financial support for all subjects deemed by the investigator 
and/or treating physician to be in need of ongoing treatment following their participation in 
study A1281198.  The support may be applied to the cost of treatment with an alternative 
medication approved and marketed within your country for the acute treatment of pediatric 
Bipolar I Disorder (for the U.S. including lithium, Risperdal®, Abilify®, Seroquel®, or 
Zyprexa®).  The choice of treatment is to be based on the clinical judgment of the 
investigator and/or treating physician. [In some cases, subjects may be treated and managed 
by the investigator following their participation in the study; in other cases, subjects may be 
referred to another physician for post study care. The post study care program would be 
available to the subject in either situation.]
The support provided will be limited to the cost of two months of pharmacotherapy with an 
approved medication within your country. The rationale for limiting support to two months 
of pharmacotherapy is based on the results of controlled clinical studies of medications 
approved for acute treatment of pediatric mania, clinical practice, and practice parameters 
promulgated by the American Academy of Child and Adolescent Psychiatry.11 Controlled 
studies of acute treatment of manic episodes in youth have ranged from 2 to 4 weeks in 
duration.12-16  After 3-4 weeks of treatment with either Zyprexa®, Seroquel®, Risperdal® or 
Abilify®, 45% to 64% of subjects on active treatment responded with a ≥50% decrease in 
severity of their manic symptoms compared to baseline.13-15  
On the other hand, 36% to 55% of subjects in these clinical studies continued to have 
substantial symptoms of mania at the end of the study, due either to a less-than-optimal 
treatment response or to poor toleration.  In addition, a proportion of subjects in each study 
early terminated, in some cases due to side effects.  Thus, some subjects exiting from the 
A1281198 study may require treatment beyond 4 weeks or may need to be switched to an 
alternative therapy, before their acute symptoms can be controlled. 


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For all these reasons taken together, it appears both clinically prudent and ethical to offer 
support for up to two months continued treatment with an approved medication to the 
participants in study A1281198 who are not eligible for or elect not to participate in the open 
level extension study A1281201. This level of support for continued treatment of the study 
subjects is consistent with the available clinical data and standard of care, without -providing 
inappropriate incentives for eligible patients to participate in the study.
The post-study treatment program is available only in countries where there are marketed 
approved medications for the treatment of pediatric bipolar disorder.  The financial support 
provided through the post study care program cannot be applied for the use of ziprasidone in 
the US as it is not approved in this patient population in the US and thus is an investigational 
agent.
The investigator and/or treating physician who is managing the subject following his/her 
participation in study A1281198 will be obligated to submit invoices or receipts documenting 
that the provided funds were applied as required to support the ongoing treatment of the 
study participants.
Subjects will not be monitored by Pfizer during their participation in the post study care 
program and no data will be collected on their treatment, clinical response, and safety beyond 
that required during their participation in the A1281198 study.  The active reporting period 
for Serious Adverse Events (SAEs) as described in Section 8.2 of the protocol (which 
extends to 28 days following the last dose of study drug) will be observed, however.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.
In order to achieve a reasonable distribution of subjects in the different weight categories, an 
enrollment target of no less than 20% will be set for both weight categories.  Since weight 
and age are generally correlated, it is expected this will also lead to an acceptable distribution 
of subjects across the age range.  Enrollment will be monitored to ensure that an appropriate 
distribution of age and weight is maintained.
Enrollment is competitive and enrollment at each site will depend on the capabilities of each 
site.  The number of enrolled subjects is not pre-specified for any individual site.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study.  A statement that 
the subject was eligible to enter the clinical trial should be completed by the investigator and 
included in the subject’s source documentation.


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There may be instances where siblings, or other subjects living in the same home or having 
the same caregiver, may both be eligible to enroll in the study. 
There is an inherent risk of mis-dosing when more than one subject living in the same home 
is enrolled at the same time.  This also includes subjects from separate households that have 
the same caregiver.  In order to mitigate any risk with dosing, only one subject that shares a 
household/caregiver should be enrolled during any given timeframe.  If another subject meets 
all inclusion/exclusion criteria for the study, that subject may also be enrolled if the 
enrollment periods do not overlap.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of personally signed and dated informed consent document by the legal 
representative and an assent document by the subject indicating that the subject and a 
legal representative have been informed of all pertinent aspects of the study.
2. Subjects and their legal guardians who are willing and able to comply with scheduled 
visits, treatment plan, laboratory tests, and other study procedures.
3. In-patient and/or out-patient male and female subjects aged 10-17 (inclusive) at 
screening.
4. Primary diagnosis of Bipolar I Disorder (current or most recent episode manic), as
defined by DSM-V criteria and confirmed by the Schedule for Affective Disorders 
and Schizophrenia for School Age Children (K-SADS).  Current symptoms 
supporting the diagnosis must have been present for at least 7 days prior to screening.
5. YMRS score 17 at the screening and baseline visits.
6. In the investigator’s opinion, the subject must be likely to benefit from therapy with 
an atypical antipsychotic drug.
7. Body Mass Index (BMI) z-score between –1.65 and +2.00, inclusive.
8. Subject must be willing and able to discontinue any medications that are prohibited in 
this study.  Any such medications must be discontinued (according to the timeframes 
in Section 5.5) prior to baseline.
Subjects who are receiving prohibited medications are to be considered for the 
protocol only if discontinuation of the medication does not compromise the welfare of 
the subject and/or alternative medication that is allowed by the protocol is available 
and appropriate for the subject. 
Psychotropic medications should be tapered down per accepted medical practice and 
the specific package insert instead of being abruptly discontinued.


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If psychotherapy has been ongoing for 3 months prior to the screening visit, it can be 
continued during the study provided there is no increase in the frequency or duration 
of the psychotherapy or change in the type of psychotherapy being provided.
9. All male and female subjects who are sexually active and/or their legal guardians, as 
appropriate, must agree that a highly effective method of contraception be used 
throughout the study and for 28 days after the last dose of assigned treatment. 
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Subjects who are investigational site staff members directly involved in the conduct 
of the trial and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the trial.
2. Subjects who are clinically stable on treatment regimens that are being well tolerated.
3. Subjects with substance-induced psychotic disorder or whose behavioral disturbance 
is thought to be due to substance abuse.
4. Subjects with DSM-V defined Substance Use Disorder (including psychoactive 
substance or alcohol use disorders) within the preceding 1 month of screening (does 
not apply to nicotine or caffeine). 
5. Subjects who are judged by the investigator as being at imminent risk of suicide. 
6. Subjects who are judged by the investigator as being at imminent risk of homicide.
7. Subjects should be excluded or a risk assessment should be done to verify that it is 
safe for the subject to participate in the trial if the subject’s responses on any of the 
screening instruments or other screening information based on the investigator’s 
judgment indicate:

A suicide ideation associated with actual intent and a method or plan at any time 
in their lifetime such that a positive response (‘Yes’) is made on items 4 or 5 of 
the suicidal ideation subscale of the C-SSRS; 

Any lifetime history of suicide behaviors such that a determination of ‘yes’ is 
made to any of the suicide behavior items of the C-SSRS.Subjects with significant 
Intellectual Disability (ie, Intelligence Quotient (IQ) <70) that would interfere 
with study conduct or with the interpretation of the study assessments.
8. Subjects with significant Intellectual Disability (ie, Intelligence Quotient (IQ) <70) 
that would interfere with study conduct or with the interpretation of the study 
assessments.


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9. Subjects with Autism Spectrum Disorder (including autistic disorder, Rett syndrome, 
childhood disintegrative disorder, pervasive developmental disorder – not otherwise 
specified (PDD-NOS), Asperger syndrome). 
10. Subjects with Disruptive Mood Dysregulation Disorder.
11. Subjects with schizophrenia, schizoaffective disorder, schizophreniform disorder, or 
delusional disorder.
12. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study.
13. Subjects with controlled or uncontrolled Type 1 diabetes.
14. Subjects with Type 2 diabetes unless diagnosed ≥6 months prior to screening and on a 
stable, well controlled treatment regimen (ie, diet and/or oral hypoglycemic agents; 
insulin use is considered exclusionary).
15. Subjects with a history of seizure or epilepsy.
Subjects with a history of febrile seizures are eligible if no seizures have occurred 
during the last 3 years.
16. Subjects with a history of syncopal episodes (sudden loss of consciousness with loss 
of postural tone and not preceded by a pre-syncopal phase) or unexplained loss of 
consciousness. 
Subjects with a history of occasional syncopes of probable vasovagal origin (onset 
not sudden but preceded by a pre-syncopal phase, presence of predisposing factors 
such as blood sampling procedure, standing, hot shower, hair curling, etc) are 
eligible.
17. Subjects with any medical condition or dietary habit that has a significant potential to 
alter the absorption of the study drug; or subjects taking any medication that may alter 
drug absorption (eg, anorexia nervosa, bulimia, chronic use of laxatives).
18. Subjects with uncorrected hypothyroidism or hyperthyroidism or whose thyroid 
function and medication regimen have been stable less than 1 month prior to 
screening.
19. Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) values ≥2x and 
total bilirubin values ≥1.5x the upper limits of normal.


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Subjects with an isolated increase of unconjugated bilirubin (Gilbert’s syndrome) are 
eligible.
20. Subjects with a history of chronic hepatitis, known serologic evidence of acute 
hepatitis or chronic hepatitis (positive hepatitis B virus surface antigen (HbsAg)), or 
subjects with known hepatitis C antibodies and elevated LFTs.
21. Subjects known to be Human Immunodeficiency Virus (HIV) positive.
22. Subjects with clinically significant hypokalemia or hypomagnesemia not corrected 
and stabilized by the addition of dietary supplements or some other corrective 
measure prior to baseline.
23. Subjects with a history of significant cardiovascular disease, including conditions that 
have previously required treatment or acute evaluation, or significant concurrent 
cardiovascular disease, including hypotension, congestive heart failure, or congenital 
heart disease.
Non-clinically significant sinus bradycardia or sinus tachycardia will not be 
considered significant medical illnesses and would not exclude a subject from the 
study. 
Isolated atrial septal defect (ASD), ventricular septal defect (VSD, or patent ductus 
arteriosus (PDA) will not be considered significant medical illnesses if they are 
surgically corrected.
24. Subjects with a history of cardiac arrhythmias, conduction abnormalities or known 
personal history of QT prolongation (including congenital long QT syndrome).
25. Subjects with a known genetic risk for prolonged QT syndrome.
26. Subjects with a clinically significant ECG abnormality at screening or baseline.
27. Subjects with a QTc (Fridericia) 450 msec at screening or baseline, which is still 
prolonged on repeat ECG.
28. Subjects taking any medications that are prohibited (see Section 5.5).
29. Subjects who are taking or have previously received clozapine.
30. Use of a depot antipsychotic within 4 weeks, or a monoamine oxidase inhibitor, 
Abilify® (aripiprazole) or Prozac® (fluoxetine) within 2 weeks prior to baseline.
31. Subjects known by medical history or hospitalization records to have used 
phencyclidine within the 30 days prior to screening.
32. Subjects requiring treatment with drugs which have been consistently observed to 
prolong the QT interval (see Section 5.5). 


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33. Subjects with history of antipsychotic-induced EPS that does not respond to 
anti-parkinsonian medication.
34. Subjects with a prior episode of neuroleptic malignant syndrome or prior 
hypersensitivity to antipsychotic agents.
35. Subjects known to be allergic to ziprasidone.
36. Subjects with a history of non-responsiveness to ziprasidone after an adequate 
treatment period at a dose between 40-80 mg daily for subjects weighing <45 kg and 
120-160 mg daily for subjects weighing ≥45 kg.
37. Subjects currently receiving ziprasidone 30 days prior to screening.
38. Participation in other studies involving investigational drug(s) (Phase 1-4) within 
30 days before the current study begins and/or during study participation.
39. Pregnant females; breastfeeding females; males and females who are sexually active 
who are not using highly effective contraception or not agreeing to continue highly 
effective contraception for 28 days after last dose of assigned treatment. 
40. Subjects that have had unprotected sex within the last 2 weeks prior to screening and 
do not have 2 negative pregnancy tests two weeks apart are not eligible to receive 
study drug.
41. Siblings, or other subjects living in the same home or having the same caregiver 
during the same enrollment period.
4.3. Randomization Criteria 
At the baseline visit, subjects must continue to meet all inclusion and exclusion criteria in 
order to qualify for randomization.
4.4. Life Style Guidelines
All male and female subjects who, in the opinion of the investigator, are biologically capable 
of having children and are sexually active, must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 28 days after the last dose of investigational product.  Subjects who are not 
sexually active (are abstinent) will not be required to use contraception.  The investigator, in 
consultation with the subject, will select the most appropriate method of contraception for the 
individual subject from the permitted list of contraception methods, and instruct the subject 
in its consistent and correct use.  The investigator, at each study visit, will confirm and 
document consistent and correct use.  In addition, the investigator will instruct the subject to 
call immediately if the selected birth control method is discontinued or if pregnancy is known 
or suspected. 


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To improve compliance with contraception, the investigator should, as permitted by local 
law, provide: (a) confidential contraception counseling and (b) assistance accessing 
additional reproductive services, if needed. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided the subject remains on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository).
4. Male sterilization with appropriately confirmed absence of sperm in the 
post-vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy.
4.5. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the study manual and Study Team on 
Demand (SToD) system’.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study number, 
contact information for the investigational site and contact details for a help desk in the event 
that the investigational site staff cannot be reached to provide advice on a medical question 
or problem originating from another healthcare professional not involved in the subjects 
participation in the study.  The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the investigational site and 
the study team are not available.  It is therefore intended to augment, but not replace the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The help desk 
number is not intended for use by the subject directly and if a subject calls that number they 
will be directed back to the investigational site.


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5. STUDY TREATMENTS
5.1. Allocation to Treatment
Subjects will be assigned a single subject identification number which will be obtained at the 
time of screening using the Interactive Voice Response System (IVRS)/Interactive Web 
Response System (IWRS) and retained throughout the study.  A separate randomization 
number will be assigned to subjects who meet the inclusion/exclusion criteria by the 
IVRS/IWRS at randomization and will be recorded on the case report form (CRF).  Subjects 
will be centrally randomized to receive 1 of 2 treatment arms (ziprasidone or placebo) in a
1:1 ratio according to a computer generated pseudo-randomization code using the method of 
permuted blocks.
5.2. Breaking the Blind
The study will be subject, investigator, and sponsor blinded. 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind.  The method will be an electronic process utilizing the IVR/IWR system.  Blinding 
codes should only be broken in emergency situations for reasons of subject safety.  
Whenever possible, the investigator or sub-investigator consults with a member of the study 
team prior to breaking the blind.  When the blinding code is broken, the reason must be fully 
documented and entered on the case report form.
5.3. Drug Supplies
5.3.1. Formulation and Packaging
Study medication will be provided by Pfizer and will include oral ziprasidone capsules of 
20 mg, 40 mg, 60 mg, and 80 mg strength or matching placebo capsules. All medication will 
be packaged in child resistant blister cards with columns for AM and PM capsules.
Two different types/designs of blister cards will be provided over the course of the study: a 
titration card design and a fixed dose card design.  Each card will contain medication for 
7 days plus 3 additional days.  All child resistant blister cards will have 1 capsule available 
for the AM and 1 capsule for the PM administration of each day.  Each AM or PM column 
will contain either a 20 mg, 40 mg, 60 mg or 80 mg ziprasidone capsule (or matching 
placebo). 
Titration cards will be provided for the first week of treatment for subjects weighing ≥45 kg 
and those weighing <45 kg. Subjects weighing ≥45 kg will also receive a second titration 
card at Day 8/Visit 3 for the second week of treatment.  Subjects weighing <45 kg will not
receive a titration card at Day 8/Visit 3; instead they will receive a fixed dosing card which 
will allow them either to continue on their current dose or to change to a higher or lower 
dose, depending on the clinical judgment of the investigator.


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Titration Card Container Types
Active or Placebo (separate cards for 
Day 1/Visit 2 and Day 8/Visit 3)
45 kg body weight
Active or Placebo (for Day 1/Visit 2 only)
<45 kg body weight
In order to accommodate the flexible dosing permitted by the protocol, 7 types of fixed 
dosing cards, each with a different total daily dose of study drug, will be provided as 
illustrated below for both active and placebo capsules:
Fixed Dose Card Container Types
Total Daily Dose
AM Dose
PM Dose
40 mg
20 mg
20 mg
60 mg
20 mg
40 mg
80 mg
40 mg
40 mg
100 mg
40 mg
60 mg
120 mg
60 mg
60 mg
140 mg
60 mg
80 mg
160 mg
80 mg
80 mg
5.3.2. Preparation and Dispensing
Study medication will first be dispensed at the baseline visit (Day 1) after all baseline 
assessments have been completed.  Treatment assignments will be made in accordance with 
the randomization sequence.  Every blister card supplied to the site will have a unique 
number.  The site will select a weight-based dosing regimen within the IVR/IWR system, and 
the IVR/IWR system will assign a container number that contains the indicated regimen.  
The weight-based dosing regimen selected at the start of the trial will continue to be applied
throughout the trial; weight fluctuations of the subjects will not be considered to reassign a 
subject to a different weight based dosing group (ie, 45 kg body weight or <45 kg body 
weight).
At each subsequent medication dispensing visit (Day 8/Visit 3, Day 15/Visit 4, and 
Day 22/Visit5), subjects will be assigned one blister card for the following study week.  The 
IVR/IWR system will cap the total daily dosage allowed so subjects cannot be prescribed a 
dose higher than the maximum dose allowed per protocol (ie, subjects <45 kg cannot exceed 
80 mg total daily dose and subjects 45 kg cannot exceed 160 mg total daily dose).  The 
system will also not allow fixed dosing cards to be dispensed when there is an incremental 
jump of more than 20 mg/day compared to the last fixed dosing card dispensed
(ie, a 120 mg/day fixed dose card could not be dispensed if the last fixed dose card dispensed 


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was an 80 mg/day card). The only exception to this rule is for subjects 45 kg where an 
increase from 120 mg/day to 160 mg/day will be allowed on Day 14 of the study. In
addition, the IVR/IWR system will not allow more than one blister card at a time to be issued 
to a subject.
On Day 1 (Baseline Visit), a single titration card will be dispensed based on the subject’s 
weight (subject 45 kg or <45 kg) for the first week of dosing (see Table 1 and Table 2
below).  The titration cards that will be used for the first week of the trial will have a 
maximum of 80 mg/day for subjects 45 kg and a maximum of 60 mg/day for subjects 
<45 kg. 
Table 1.
45 kg Titration Regimen for Day 1/Visit 2
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
-
20
20
2
20
20
40
3
20
20
40
4
20
40
60
5
20
40
60
6
40
40
80
7
40
40
80
8
40
40
80
9
40
40
80
10
40
40
80
Table 2.
<45 kg Titration Regimen for Day 1/Visit 2
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
-
20
20
2
20
20
40
3
20
20
40
4
20
20
40
5
20
40
60
6
20
40
60
7
20
40
60
8
20
40
60
9
20
40
60
10
20
40
60
At Day 8/Visit 3, subjects weighing 45 kg would typically receive a second titration card 
(see Table 3 below) which will increase their total daily dose to 120 mg/day (reached on 
Day 10 of the study). 


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Table 3.
45 kg Titration Regimen for Day 8/Visit 3
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
40
60
100
2
40
60
100
3
60
60
120
4
60
60
120
5
60
60
120
6
60
60
120
7
60
60
120
8
60
60
120
9
60
60
120
10
60
60
120
However, the investigator can also choose to provide a fixed dose card with a different daily 
dose, eg, 100 mg/day or 80 mg/day (see Table 4 and Table 5 below), if in his or her clinical 
judgment that is the more appropriate choice. 
Table 4.
100 mg Fixed Dose Regimen
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
40
60
100
2
40
60
100
3
40
60
100
4
40
60
100
5
40
60
100
6
40
60
100
7
40
60
100
8
40
60
100
9
40
60
100
10
40
60
100


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Table 5.
80 mg Fixed Dose Regimen
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
40
40
80
2
40
40
80
3
40
40
80
4
40
40
80
5
40
40
80
6
40
40
80
7
40
40
80
8
40
40
80
9
40
40
80
10
40
40
80
Subjects weighing 45 kg should be provided the 160 mg/day fixed dose card (see Table 6)
only if they have tolerated 120 mg/day; in addition, the 160 mg/day fixed dose card should 
not be issued before Day 14 of the study.
Table 6.
160 mg Fixed Dose Regimen
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
80
80
160
2
80
80
160
3
80
80
160
4
80
80
160
5
80
80
160
6
80
80
160
7
80
80
160
8
80
80
160
9
80
80
160
10
80
80
160
At Day 8/Visit 3 , subjects weighing <45 kg can either be maintained on their Day 7 dose 
(see Table 7) or the dose can be increased to 80 mg/day (see Table 5) or decreased to 
40 mg/day (see Table 8). The investigator will decide which fixed dose blister card to 
provide to the subject for the following week, based on clinical judgment.


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Table 7.
60 mg Fixed Dose Regimen
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
20
40
60
2
20
40
60
3
20
40
60
4
20
40
60
5
20
40
60
6
20
40
60
7
20
40
60
8
20
40
60
9
20
40
60
10
20
40
60
Table 8.
40 mg Fixed Dose Regimen
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
20
20
40
2
20
20
40
3
20
20
40
4
20
20
40
5
20
20
40
6
20
20
40
7
20
20
40
8
20
20
40
9
20
20
40
10
20
20
40
Only site personnel according to their role as determined on the site delegation log may 
dispense study medication cards. Subjects will be instructed to take one capsule in the 
AM and one capsule in the PM from each assigned blister card.
Subjects are not allowed to leave the clinic with more than one blister card in their 
possession.


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5.3.3. Administration
As study drug administration is complex, the parent or guardian should closely supervise 
dosing throughout the study, especially during the titration period.  One capsule is taken in 
the morning and one capsule in the evening about 12 hours apart. If a dose is missed, the 
missed dose should be taken as soon as possible, but the AM and PM doses should be 
separated by a minimum of 4 hours. 
All study medication is to be taken with food.  Capsules are to be taken intact.  Swallow the 
capsule whole.  Do not crush or chew the capsule.
In general, the target dose should be attained by Days 7-14.  For subjects with a body 
weight ≥45 kg, the target dose range is 120-160 mg/day.  A dose of 160 mg/day should not 
be achieved before Day 14 of treatment. 
For subjects with a body weight <45 kg, the target dose range is 60-80 mg/day.  A dose of 
80 mg/day should not be achieved before Day 8 of treatment.
5.3.3.1. Baseline (Day 1)/Visit 2
At the baseline visit, after all baseline assessments have been completed, each randomized 
subject will receive one titration blister card for the first week of treatment, which will be 
assigned based on the subject’s body weight (<45 kg or 45 kg).  The body weight used to 
determine this assignment will continue to be applied throughout the trial; weight 
fluctuations of the subject will not be considered to reassign a subject to a different weight 
based dosing group.  The investigator or a staff member will explain the titration card to each 
subject and his/her parent or guardian, and clearly specify that one capsule must be taken 
from the AM column with food and one capsule from the PM column with food, sequentially 
from each row (day) until the next study visit.  (See Table 1 and Table 2 for the 
Day 1/Visit 2 titration blister cards).  All subjects will take the first dose of study medication 
(20 mg or placebo) from the Day 1 row (PM column) in the afternoon or evening of the 
baseline visit.  There will be no AM dose of study medication for Day 1.  The subject’s first 
AM dose will be on Day 2.
After the baseline visit, the investigator or designated staff must be in contact with the 
subject and/or his/her parent(s) and/or guardian(s) at least once during the week, either by 
telephone or in person, to ensure that the subject is taking the proper capsules at the proper 
time and to monitor the tolerability, safety, and efficacy of the study drug.
Only the Principal Investigator (PI) or a designated medically trained sub-investigator can 
make modifications to the subject’s study drug dose.  If changes are necessary, an 
unscheduled visit is recommended so that the subject can be observed and so that changes to 
the study drug dose can be fully explained to the subject and to his/her parent(s) or 
guardian(s). 


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5.3.3.2. Day 8/Visit 3 (end of Week 1)
At Day 8/Visit 3, the investigator should review the clinical response of each subject and 
determine whether to continue the current study drug dose or to increase or decrease it. 
Subjects weighing ≥45 kg should be issued the Day 8/Visit 3 titration card (see Table 3).
However, the investigator can also choose to provide a fixed dose card with a different daily 
dose, eg, 100 mg/day or 80 mg/day (see tables Table 4 and Table 5), if in his or her clinical 
judgment that is the more appropriate choice. 
Subjects weighing <45 kg should be issued a fixed dosing card with the desired total daily 
dose for the second week of double-blind therapy (ie, either 40 mg/day, 60 mg/day, or 
80 mg/day; see Table 5, Table 7, or Table 8). 
A dose of 160 mg/day for subjects with a body weight 45 kg should not be achieved before 
Day 14 of treatment, and a dose of 80 mg for subjects with a body weight <45 kg should not 
be achieved before Day 8 of treatment.
Following the Day 8/Visit 3 clinic visit, the investigator or designated staff must be in 
contact with the subject and/or his/her parent(s) and/or guardian(s) at least once during the 
week, either by telephone or in person, to ensure that the subject is taking the proper capsules 
at the proper time and to monitor the tolerability, safety, and efficacy of the study drug.
5.3.3.3. Day 15/Visit 4 (end of Week 2)
At the Day 15/Visit 4 (end of Week 2) clinic visit, the investigator should review the clinical 
response of each subject and determine whether to continue the current study drug dose or in 
the event of tolerability or safety concerns, to make a downward dose adjustment. Subjects 
should be issued a single fixed dosing card with the desired total daily dose.
In general, the subject’s dose should be kept stable during the remainder of the double-blind 
treatment period.  If clinically necessary due to safety or tolerability concerns, however, 
downward dose adjustments can be made, in which case the subject should be seen at an 
unscheduled visit so that the subject can be observed and so that changes to the study drug 
dose can be fully explained to the subject and to his/her parent(s) or guardian(s). 
5.3.3.4. Day 22/Visit 5 (end of Week 3)
At the Day 22/Visit 5 (end of Week 3) clinic visit, the investigator should review the clinical 
response of each subject and determine whether to continue the current study drug dose or, in 
the event of tolerability or safety concerns, to make a downward dose adjustment.  Subjects 
should be issued a single fixed dosing card with the desired total daily dose.


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5.3.3.5. Day 29/Visit 6 (end of Week 4)
At the Day 29/Visit 6 (end of Week 4) clinic visit, the investigator should review the clinical 
response of each subject and obtain the end of treatment assessments (see Section 6.4). The 
Day 29/Visit 6/end of Week 4 visit must be scheduled in the morning hours.  Subjects should 
be instructed to come to the visit fasting, before taking their morning study medication dose, 
since subjects will be required to take their morning medication under supervision at the site. 
5.3.3.6. Dose Reductions
If a subject with a body weight 45 kg cannot tolerate a dose of 120 –160 mg/day during the 
titration weeks, the investigator can reduce the dosage to 100 or 80 mg/day and the subject 
can remain in the study. Subjects who cannot tolerate a dose of 80 mg/day will discontinue 
from the double blind study and will not be eligible for continuation of treatment in the 
open-label extension study. If a subject weighing <45 kg cannot tolerate a dose of 60 mg/day 
during the Week 1 titration, the investigator can reduce the total daily dosage to 40 mg/day. 
Subjects who cannot tolerate a dose of 40 mg/day will discontinue from the double blind 
study and will not be eligible for continuation of treatment in the open-label extension study.
In general, dose reductions should not exceed 40 mg/day unless a subject is experiencing 
adverse events necessitating a faster dose reduction.
Any time there is a post-titration period dose change, it is imperative that the date on which 
subjects begin taking a different dose is recorded. Only the PI or a designated medically 
trained sub-investigator can make modifications to the subject’s dose.  If changes are 
necessary, unscheduled visits are recommended to be scheduled so that the subject can be 
observed and so that changes to the dosing plan can be fully explained to the subject and to 
his/her parent(s) or guardian(s). 
5.3.4. Compliance
The investigator must maintain a complete and current dispensing and inventory record that 
has been supplied by the sponsor.
Study personnel at the site should monitor compliance at each study visit according to the 
Schedule of Activities by comparing the returned study drug contained within the blister 
cards keeping in mind the prescribed dose with the dose information reported by the subject 
on the diary card.  Discrepancies between returned capsule counts from the blister cards and 
subject-reported dose information on the subject diary cards should be reconciled with the 
subject and/or legal guardian during the office visit.  Compliance and any unresolved 
discrepancies will be documented in the source documents and on the Investigational Product 
Accountability Log.  The study drug CRF page should reflect the reconciled dose 
information provided by the subject and/or legal guardian.
In addition, photocopies should be made of both sides of the returned blister cards. The 
photocopies should be dated and signed and kept as part of the source documentation.


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The subject diary cards and the photocopies of the blister cards will serve as the source 
documentation of what medication was taken as the actual blister cards will eventually be 
destroyed according to drug accountability procedures (see Section 5.4).  Information from 
the subject diary card will be included on the study drug CRF page.
A subject will be considered non-compliant with respect to dosing if the subject misses more 
than 20% of their scheduled doses over the entire study. Such a condition will be considered 
a protocol violation and the subject will be excluded from the per protocol (PP) analysis set.
5.4. Drug Storage and Drug Accountability
Upon receipt of the investigational product shipment, the investigator or an appropriate site
representative (eg, pharmacist/dispenser) will verify the condition of the study supplies and 
document per instructions in the pharmacy binder. 
The investigator or an approved representative (eg, pharmacist), will ensure that all study 
drug is stored in a secured area, under recommended storage conditions and in accordance 
with applicable regulatory requirements.  Investigational product is to be stored at 15-25°C 
(59-77°F).  Specific details on storage requirements can be found in the pharmacy binder.
Drug should be stored in accordance with the drug label.
Storage conditions stated in the Single Reference Safety Document (SRSD) (ie, Investigator 
Brochure (IB), Core Data Sheet (CDS), United States Package Insert (USPI), Summary of 
Product Characteristics (SPC), or Local Product Document (LPD)) will be superseded by the 
label storage.
Investigators and site staff are reminded to check temperatures daily (ie, manually or by 
using alarm systems to alert of any excursions) and ensure that thermometers are working 
correctly as required for proper storage of investigational products. These include 
thermometers for both the room storage and refrigerator storage.  Any temperature 
excursions should be reported to the sponsor.
The investigational product(s) must be stored as indicated. Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the sponsor. 
Once a deviation is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.
Investigational product use will be accounted for in the CRF and drug accountability 
inventory forms as instructed by Pfizer. All drug supplies will be returned to Pfizer or its 
agent or destroyed on site according to site specific procedures.
5.5. Concomitant Medication(s)
The start and stop date, if applicable, for all concomitant medications received for the disease 
under study within 1 year before screening and for all other concomitant medications within 
90 days before screening until the last scheduled visit will be recorded on the appropriate 
CRF. 


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Subject must be willing and able to discontinue any medications that are prohibited in this 
study (see table below).  Any such medications must be discontinued according to the 
timelines in the table prior to the administration of study medication. Exclusionary 
medications may have to be tapered instead of being abruptly discontinued if appropriate, in 
accordance with accepted medical practice.
Lorazepam (oral or intramuscular) may be used pro re nata (PRN) for anxiety or agitation up 
to a maximum of 2 mg/day but should not be given within 6 hours prior to an efficacy 
assessment.  If possible, the investigator should start with a low dose of lorazepam to control 
a subject’s symptoms, and then increase incrementally up to a total of 2 mg/day, if needed.  
A comparable benzodiazepine may be used in place of lorazepam with prior permission from 
Pfizer.  The dose administered should be therapeutically comparable to that for lorazepam. 
For the treatment of insomnia, lorazepam may be used as specified above, or alternatively, 
diphenhydramine or zolpidem, as determined by the principal investigator, are permitted on a 
PRN basis, but should not be given within 6 hours prior to efficacy assessments being 
performed.
For the treatment of extrapyramidal symptoms that may appear during the trial, benztropine, 
benzhexol, other anticholinergics, or propranolol may be used based on the discretion of the 
principal investigator.
Subjects should be instructed not to take any medications, including over-the-counter 
products, without first consulting the investigator, unless such medications are for emergency 
use.
The chronic use of certain medications (some hormones, antihypertensives, diuretics, and 
oral hypoglycemics) are allowed if the subject was prescribed these medications at least 
30 days prior to screening, the subject’s condition is stable, and the dose is stabilized prior to 
the first dose of study medication.
Any questions about whether use of a concomitant medication or treatment is prohibited or 
permitted during a subject’s study participation should be discussed with the sponsor.  The 
table below is not all inclusive so contact the sponsor with questions. 


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Prohibited/Concomitant Medication Table
The following agents are prohibited during the trial and must be discontinued at least 4 ½ half lives (or 
10 days, whichever is less) before baseline:

Antipsychotic agents (see aripiprazole exception below).

Mood stabilizers (ie, lithium and anticonvulsants, such as lamotrigine and depakote).

Stimulants (including but not limited to: amphetamines, dexmethylphenidates, 
dextroamphetamines, lisdexamfetamine dimesylates, methamphetamines, and methylphenidates).

Antidepressants (see monoamine oxidase (MAO) inhibitors, or fluoxetine exception below).

Anxiolytics (benzodiazepines and nonbenzodiazepines except those permitted per protocol).

Sedative/hypnotics (except those permitted per protocol).

Nootropics (such as hopantenic acid, nikethamide, pyracetam, phenylpyracetam).

Supplements/herbal agents with CNS effect (ie, Gamma-aminobutyric acid (GABA), glycine, 
dehydroepiandrosterone (DHEA), St. John’s Wort).

Biotin (dose exceeding 100mcg daily) Children multivitamin levels allowed.

Sympathomimetics (except those permitted per protocol).

Antiemetics (dopamine antagonists such as prochloperazine and metoclopramide).

Propranolol as an antihypertensive, reserpine, clonidine, and methyldopa.

Any medications that have been consistently observed to prolong the QT interval, including:

The antiarrhythmic agents: dofetilide (Tikosyn), sotalol (Betapace), quinidine 
(Quinaglute), Class 1A and III antiarrhythmics;

The antipsychotics: mesoridazine (Serentil), thioridazine (Mellaril), chlorpromazine 
(Thorazine), droperidol (Inapsine), pimozide (Orap);

The anti-infectives: sparfloxacin (Zagam), gatifloxacin (Tequin), moxifloxacin 
(Avelox), pentamidine (Pentam);

The anti-malarials: halofantrine (Halfan); mefloquine (Lariam), arsenic trioxide 
(Trisenox), levomethadyl acetate (Orlaam), dolasetron mesylate (Anzemet), 
probucol (Lorelco-an antilipemic), tacrolimus (FK 506, Prograf).

Recreational drugs.
The following medications are cited in the exclusion criteria section as being prohibited and/or the 
medications must be discontinued for a longer length of time before baseline:

Past or present use of clozapine.

Depot antipsychotic within 4 weeks prior to baseline.

Monoamine oxidase inhibitors within 2 weeks prior to baseline.

Abilify® (aripiprazole) within 2 weeks prior to baseline.

Prozac® (fluoxetine) within 2 weeks prior to baseline.

Phencyclidine within 30 days prior to screening.

Commercially available ziprasidone use 30 days prior to screening.
The following types of medications are allowed if taken at least 30 days before screening, the subject’s 
condition is stable, and the dose is stabilized before the first dose of study medication:

Antihypertensives.

Antianginal agents.

Antiarrhythmics (except QTc prolonging).


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
Anticoagulants.

Steroids.

Theophylline.

Replacement hormones.

Oral hypoglycemic.
The following medications are allowed:

For anxiety or agitation, lorazepam up to 2 mg/day may be used as detailed in the protocol.

For insomnia, lorazepam, diphenhydramine or zolpidem may be used as detailed in the protocol.

For the treatment of extrapyramidal symptoms, benztropine, benzhexol, other anticholinergics or 
propranolol as detailed in the protocol.

Aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild to 
moderate pain relief.

Loratadine, desloratidine, fexofenadine or cetirizine for allergies.

Common cold preparations are permitted on a PRN basis.  Subjects should not take these 
medications within 6 hours before any visit. 

Laxatives (occasional use).

Antacids (at least 4 hours before or after study drug administration).

PRN use or topical or inhaled steroids.
6. STUDY PROCEDURES 
The subject and the legal representative must understand the nature of the study and be able 
to comply with protocol requirements.  The investigator, or a person designated by the 
investigator, will obtain written informed consent from each subject's legal representative 
and a written assent from the subject before any trial specific activity is performed.  Subjects 
who turn 18 years old during the study need to give a written consent unless State law states 
otherwise, and such State law shall apply.
The subject should be assigned a subject number from the IVR/IWR system after obtaining 
informed consent.  AEs must be recorded from the time that the informed consent is signed.
Every effort should be made to bring the subject back to the office on the designated study 
days; however, office visits will have a ±3 day visit window to allow for slight variations in 
subject schedules unless approved on an individual subject basis by the sponsor.  When 
scheduling subsequent visits, the overall treatment period in the protocol should be 
maintained.
6.1. Screening
Screening procedures are to be performed within 14 days of the baseline visit (Visit 2), 
unless approved on an individual subject basis by the sponsor.  Screening procedures may be 
completed over 1 or multiple days based on the needs of the site and/or the 
subject/parent/guardian.


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The following information/assessments will be collected/performed during the screening 
period:
•
Subject demography (including date of birth, gender, and race).
•
Determine diagnostic eligibility with clinical interview/confirm diagnosis using the 
K-SADS/prepare diagnostic narrative for external review.
Determination of a Bipolar I Disorder (current or most recent episode manic)
diagnosis will be based on a clinical interview conducted by a child and adolescent 
psychiatrist (or in the case of countries outside the US, the local country equivalent in 
education and training) and confirmed by administration of the K-SADS.  The 
K-SADS must be administered by a child and adolescent psychiatrist (or in the case 
of countries outside the US, the local country equivalent in education and training)
who may be the PI or sub-PI or by a PsyD- or PhD-level clinical psychologist trained 
in child development.  See Section 7.4.
Diagnostic assessments will also be reviewed by an external member of an expert 
panel.  A brief narrative describing the symptoms of the subject which support the 
diagnosis will be submitted to external experts for verification before the investigator 
is allowed to randomize the subject composed by the child and adolescent psychiatrist
(or in the case of countries outside the US, the local country equivalent in education 
and training) at the site. 
If the subject meets the DSM-V criteria for Bipolar I Disorder (current or most recent 
episode manic), the investigator, taking into account the welfare of the subject, will 
establish whether the subject is willing and/or able to wash-out any exclusionary 
medications.
•
Medical and psychiatric history of subject and family history.  Presence of chronic 
conditions and/or medical history of significance including relevant surgical 
procedures, including start date will be collected.  For conditions identified at 
screening, the investigator must use medical judgment to determine whether to record 
the condition as a medical history finding or as an AE.  Medical history conditions 
that worsen after the informed consent is signed are considered AEs.
•
Efficacy assessments: YMRS, CGI-S, and 
  See Section 7.3.
•
Full physical examination, including body temperature.  See Section 7.2.3.
•
Height, weight, BMI, BMI z-score, and waist circumference.  See Section 7.2.4.
•
12-lead ECG.  See Section 7.2.6.
•
Blood pressure and pulse.  See Section 7.2.5.
•
Child Depression Rating Scale – Revised (CDRS-R).  See Section 7.2.7.
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
Columbia-Suicide Severity Rating Scale (C-SSRS); see Section 7.2.9.

Laboratory evaluations.  Obtain blood and urine samples for blood chemistry, 
hematology, urinalysis, hormones (free T4 & thyroid-stimulating hormone (TSH), 
prolactin), and hepatitis serology. See Section 7.2.1.

Fasting blood samples for glucose, lipid profile, insulin, glycosylated hemoglobin
(HbA1c).  See Section 7.2.1.

Urine sample for urine drug screen.  See Section 7.2.2.

For female subjects, a urine pregnancy test should be performed followed by a serum 
pregnancy test if the urine test is positive.  (Both the urine and serum pregnancy tests 
must have a sensitivity for detection of human chorionic gonadotophin (hCG) of at 
least 25 mIU/mL). In addition, if a subject is not sure whether they might be pregnant 
at the time of screening, ie, they have had unprotected sex within the last 2 weeks 
prior to screening, then that subject would be required to have 2 negative pregnancy 
tests two weeks apart before they could receive study drug. See Section 7.1.

Prior and concomitant medications.

Assess and record any reported AEs.
6.1.1. Screen Fail Subject
Screen failure subjects are defined as:

A subject who does not meet one or more inclusion criteria or meets one or more 
exclusion criteria will be considered a screen failure.

If a subject cannot return for the baseline visit within the protocol specified screening 
period, the subject will be considered a screen failure.
Screen failure subjects may re-screen at a later date.  If a subject chooses to re-screen, a 
second informed consent/assent must be obtained and documented, a new subject number 
must be assigned, and all screening tests and procedures must be repeated.  A subject may 
not re-screen more than once.
6.2. Visit 2 (Day 1) - Baseline
The baseline visit will occur 1-14 days after the screening visit, allowing time for wash-out 
of any antipsychotics and/or exclusionary medications and for laboratory results to be 
received and repeated, if necessary, to confirm eligibility. The following 
information/assessments will be collected /performed during the baseline visit:

Confirm all inclusion/exclusion criteria are met.

12-lead triplicate ECG.  See Section 7.2.6.


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•
Blood pressure and pulse.  See Section 7.2.5.
•
Laboratory evaluations only if clinically significant abnormalities are present at 
screening.  Obtain blood and urine samples for blood chemistry, hematology, 
urinalysis, and hormones (free T4, TSH, and prolactin). See Section 7.2.1.
•
Fasting blood samples for glucose, lipid profile, insulin, HbA1c only if clinically 
significant abnormalities are present at screening.  See Section 7.2.1.
•
For female subjects, a urine pregnancy test should be performed followed by a serum 
pregnancy test if the urine test is positive.  A negative pregnancy test is required (at 
both the screening and baseline visits) before the subject may receive investigational 
product. See Section 7.1.
•
Urine sample for urine drug screen; see Section 7.2.2.
•
Efficacy assessments: YMRS, CGI-S, and 
See Section 7.3.
•
CDRS-R.  See Section 7.2.7.
•
C-SSRS. See Section 7.2.9.
•
Movement disorder scales: SARS, BAS, and AIMS.  See Section 7.2.8.
•
Record concomitant medications.
•
Assess and record any reported AEs.
•
Randomization.
•
Dispense study drug.  Subjects will receive their first capsule in the afternoon/evening
(with food) from the blister card PM column for Day 1.
•
Contact should be made with the subject by the investigator or designated staff 
member, either by telephone or in person as an unscheduled visit, after the baseline 
visit but before Visit 3 to ensure that the subject is taking the proper capsules at the 
proper time and to monitor the tolerability, safety, and efficacy of the study drug.
6.3. Treatment Period
See the Schedule of Activities for procedures to be performed at each study visit during the 
treatment period. 
6.3.1. Visit 3 (Day 8/Week 1)
•
12-lead ECG.  See Section 7.2.6.
•
Blood pressure and pulse.  See Section 7.2.5.
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
Laboratory evaluations.  Obtain blood and urine samples for blood chemistry, 
hematology, and urinalysis and in females a pregnancy test. See Section 7.2.1.

Efficacy assessments: YMRS, CGI-S, and Clinical Global Improvement Scale 
(CGI-I). See Section 7.3.

CDRS-R.  See Section 7.2.7.

C-SSRS.  See Section 7.2.9.

Movement disorder scales: SARS, BAS, and AIMS.  See Section 7.2.8.

Record concomitant medications.

Assess and record any reported AEs.

Perform drug accountability.

Dispense study drug.

Contact should be made with the subject by the investigator or designated staff 
member, either by telephone or in person as an unscheduled visit, after Visit 3 but 
before Visit 4 to ensure that the subject is taking the proper capsules at the proper 
time and to monitor the tolerability, safety, and efficacy of the study drug.
6.3.2. Visit 4 (Day 15/end of Week 2)

12-lead ECG.  See Section 7.2.6.

Blood pressure and pulse.  See Section 7.2.5.

For female subjects, a urine pregnancy test should be performed followed by a serum 
pregnancy test if the urine test is positive.  See Section 7.1.

Efficacy assessments: YMRS, CGI-S, and CGI-I. See Section 7.3.

CDRS-R.  See Section 7.2.7.

C-SSRS.  See Section 7.2.9.

Movement disorder scales: SARS, BAS, and AIMS.  See Section 7.2.8.

Record concomitant medications.

Assess and record any reported AEs.

Perform drug accountability.


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•
Dispense study drug.
6.3.3. Visit 5 (Day 22/end of Week 3)
•
12-lead ECG.  See Section 7.2.6.
•
Blood pressure and pulse.  See Section 7.2.5.
•
For female subjects, a urine pregnancy test should be performed followed by a serum 
pregnancy test if the urine test is positive.  
•
Efficacy assessments: YMRS, CGI-S, and CGI-I. See Section 7.3.
•
CDRS-R.  See Section 7.2.7.
•
C-SSRS.  See Section 7.2.9.
•
Movement disorder scales: SARS, BAS, and AIMS.  See Section 7.2.8.
•
Record concomitant medications.
•
Assess and record any reported AEs.
•
Perform drug accountability.
•
Dispense study drug.
6.4. Visit 6 (Day 29/end of Week 4) - End of Treatment (or Early Termination)
The Week 4 visit must be scheduled in the morning hours.  Subjects should be instructed to 
come to the visit fasting, before taking their morning study medication dose, since subjects 
will be required to take their morning medication under supervision at the site. 
•
12-lead triplicate ECG recording, blood pressure and pulse, 
 
 and study medication administration:
Prior to study medication dosing, all subjects will have a triplicate 12-lead ECG 
followed by blood pressure and pulse measurements (see below table for timing of 
procedures). 
Event
Time before/after dosing (hours)
Pre-dose
Triplicate 12-lead ECG*
<-0.1 hours
Blood pressure/pulse
<-0.1 hours
* Triplicate 12-lead ECG taken before blood pressure and pulse.
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6.5. Visit 7, Follow-up Visit (Day 36/end of Week 5)
Subjects will return for a post-treatment follow-up clinic visit at Week 5, if they are not 
entering the open-label extension Study A1281201.  The following procedures/assessments 
will be performed at week 5:

C-SSRS.  See Section 7.2.9.

Record concomitant medications.

Assess and record any reported AEs.

For female subjects, a urine pregnancy test should be performed followed by a serum 
pregnancy test if the urine test is positive.
Only if clinically significant abnormalities are present at Visit 6 Week 4, the following will 
be performed:

Laboratory evaluations. Obtain blood and urine samples for blood chemistry, 
hematology, urinalysis, and hormones (free T4, TSH, and prolactin). See 
Section 7.2.1.

Fasting blood samples for glucose, lipid profile, insulin, and HbA1c.  See 
Section 7.2.1.

Blood pressure and pulse.  See Section 7.2.5.

12-lead ECG.  See Section 7.2.6.

Movement disorder scales (SARS, BAS and AIMS).  See Section 7.2.8.
After the Visit 6/Week 4 visit subjects may enter the open label extension study or be 
switched to one of the alternative approved therapies for treatment of pediatric bipolar 
disorder within your country (for the U.S. including lithium, Abilify, Risperdal, 
Zyprexa, and Seroquel) if in the judgment of the investigator or treating physician, 
continued pharmacotherapy is warranted. 
Contact may occur via telephone and must occur 28 to 35 days from administration of the 
final dose of investigational product to capture any potential adverse events (see the Adverse 
Events Information section) and to confirm appropriate contraception usage (see the Life 
Style Guidelines section) for subjects who do not enter the open label extension study.
Based on accumulated safety data from the pre-marketing clinical trials with ziprasidone, 
short term treatment with ziprasidone does not appear to be associated with a marked 
withdrawal syndrome and it should be feasible and well tolerated to immediately switch the 
subjects from ziprasidone treatment to an alternative treatment.  Following the last dose of 
study drug, ziprasidone plasma concentrations should self-taper over 2 to 3 days, during 


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which time the alternative medication can be titrated up to ensure that treatment of the 
subject is not interrupted.
6.6. Unscheduled Visits
Unscheduled visits may be performed at any time during the study whenever necessary to 
assess for or to follow-up on adverse events at the subject’s request or as deemed necessary 
by the investigator.
6.7. Subject Withdrawal
The investigator is responsible for the clinical management of the subject throughout his or 
her participation in the study.  A subject should be discontinued from the study if, based on 
the investigator’s clinical judgment, it is no longer in the subject’s interest to continue.  If a 
subject is discontinued, the investigator will ensure that the subject receives appropriate 
clinical care and follow-up.  Subjects who are discontinued from the study may be eligible to 
participate in a post study care program (see Section 3.1).
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site. The investigator must determine the primary reason 
for discontinuation. If a discontinuation is due to a serious adverse event, the serious adverse 
event must be reported immediately to Pfizer. Withdrawal due to an adverse event should be 
distinguished from withdrawal due to insufficient response according to the definition of 
adverse event noted in Section 8.
Because of the placebo control being used in this trial, it is important to provide guidelines to 
investigators who, during the study, may need to determine whether a subject should be 
removed from the study as a result of insufficient clinical response (or due to safety 
considerations arising from it) or whether that subject would benefit from alternative 
therapies. These guidelines are summarized in the table below in Section 6.7.1. The table
also identifies those adverse events that require special action.
An end of treatment visit must be scheduled for any subject who discontinues early from the 
study. At this visit, all assessments scheduled for the Week 4 visit should be performed.  The 
investigator will record the reason for study discontinuation in the eCRF, provide or arrange 
for appropriate follow-up (if required), and document the course of the subject’s condition.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. Efforts to contact the subject should be fully documented in the subject’s record. In 
any circumstance, every effort should be made to document subject outcome, if possible.  
The investigator should inquire about the reason for withdrawal, request the subject to return 
all unused investigational product(s), request the subject to return for a final visit, if 
applicable, and follow up with the subject regarding any unresolved adverse events (AEs). 


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If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects who were randomly assigned and withdrawn from the study will not be replaced, 
regardless of the reason for withdrawal.
6.7.1. Specific Withdrawal Criteria
Specific adverse events and dosing response events, as shown in the table below, mandate 
withdrawal from this study.
Event
Criteria
Syncope
All syncopal episodes suggestive of cardiac arrhythmia (sudden loss of 
consciousness, loss of postural tone, and no pre-syncopal phase), except 
vasovagal syncope will be considered adverse events and the subject will be 
discontinued from the study.  Every effort should be made to obtain vital 
signs and an electrocardiogram at the time of the event.  Further evaluation, 
eg, Holter monitoring, may also be useful.  Subjects experiencing syncope 
of probable vasovagal origin (onset not sudden but preceded by a 
pre-syncopal phase, presence of predisposing factors such as blood 
sampling procedure, standing, hot shower, hair curling, etc) will also be 
considered adverse events but subjects may continue study participation 
after sponsor approval.
Prolonged 
QT
Electrocardiograms are to be reviewed and compared to baseline to assess 
potential changes. ECGs showing a QTcF of 480 msec or a suspected 
increase from baseline of 60 msec or greater must be repeated within the 
same visit.  If the QTcF value persists at 480 msec and/or the change from 
baseline persists at 60 msec, the study drug must be discontinued 
immediately and a pediatric cardiologist or an adult cardiologist 
experienced in the interpretation of pediatric ECGs should be contacted to 
discuss the ECG result.
A verified increase in QTcF of ≥60 msec or a verified occurrence of QTcF 
≥480 msec will be considered as an adverse event of QTc prolongation.  
QTcB prolongation (Bazett’s correction) will not be used to define adverse 
events; QTcB will be measured only to enable historical comparisons.
Ventricular 
arrhythmia
An ECG showing ventricular arrhythmia (except single ventricular 
extrasystoles) should be followed up with a rhythm strip ECG and Pfizer 
must be notified.  In addition, a stat over read from the central vendor 
should be requested, a pediatric cardiologist or adult cardiologist 
experienced in the diagnosis and treatment of pediatric arrhythmias should 
be consulted, and the subject monitored, as necessary.  If the ventricular 
arrhythmia is confirmed, the subject must be discontinued from the study.  


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Event
Criteria
Imminent 
Risk of 
suicide
It is expected that investigators will be assessing the risk of suicidality with 
every subject at every visit.  A subject must be discontinued from the trial 
due to imminent risk of suicide and appropriate actions should be 
undertaken whenever: (1) A subject is judged by the investigator as being at 
imminent risk of suicide at any time during the study, or (2) A subject has 
answered “yes” on items 4 or 5 of the suicidal ideation subscale of the 
C-SSRS or any behavioral questions on the C-SSRS on more than one 
occasion (ie, subject had a positive response on the C-SSRS, underwent a 
risk assessment and was allowed to continue on study, but then had a 
second positive response on the C-SSRS at a later visit).
Pregnancy
If a pregnancy occurs during the course of this trial, ziprasidone must be 
discontinued and the subject will not be eligible for the open-label study. 
Study drug must be discontinued as soon as pregnancy is suspected or a 
positive urine pregnancy test is reported.  The subject must be discontinued 
from the trial if the pregnancy is confirmed via a positive serum pregnancy 
test.
Minimum 
Total Daily 
dose
Subjects with body weight <45 kg with who cannot tolerate a dose of 
40 mg/day or greater. Subjects with body weight ≥45 kg who cannot 
tolerate a dose of 80 mg/day or greater.
Insufficient 
clinical 
response
Subjects who have insufficient treatment response and have reached their 
maximum allowed or maximum tolerated dose should be discontinued from 
the study and should return for a follow-up clinic visit as soon as possible.  
The procedures listed at Visit 6/Week 4 according to the Schedule of 
Activities should be followed.
Rescue 
Medications
Open Label 
Study
Subject requiring concomitant treatment with mood stabilizers, 
antidepressants, or stimulants.
Subjects who have insufficient treatment response at 1 week after the end of 
their titration, despite having reached their maximum tolerated dose should 
discontinue from the study and may enroll in the open-label extension trial.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.
The study team will be informed of these incidents in a timely fashion.


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7.1. Pregnancy Testing
For female subjects, a urine dipstick pregnancy test, with sensitivity of at least 25 mIU/mL, 
will be performed at all visits as specified in the Schedule of Activities.  If the urine dipstick 
test is positive, a serum pregnancy test should also be performed.  Pregnancy tests will also 
be done whenever one menstrual cycle is missed during the active treatment period (or when 
potential pregnancy is otherwise suspected), and at the end of the study to confirm the subject 
has not become pregnant during the study.  In the case of a positive hCG test, the subject will 
be withdrawn from study medication but may remain in the study.  Pregnancy tests may also 
be repeated as per request of IRB/IECs or if required by local regulations.
In addition, if a subject is not sure whether they might be pregnant at the time of screening, 
ie, they have had unprotected sex within the last 2 weeks prior to screening, then that subject 
would be required to have 2 negative pregnancy tests two weeks apart before they could 
receive study drug.
7.2. Safety Assessments
7.2.1. Laboratory Assessments
A central laboratory will be used for all clinical laboratory determinations unless a special 
test is required or a special circumstance is encountered such that timely results from a 
central laboratory are not possible.  In both these cases, an additional clinical laboratory may 
be designated by the investigator.  The investigator or other appropriate staff member should 
notify the sponsor that a local clinical laboratory is being used.  Laboratory certification and 
laboratory normal range documentation must be provided to the sponsor for all laboratories 
used other than the central laboratory.
Sample collection, storage, and shipping information can be found in the laboratory manual.
No routine laboratory assessments will be performed at Week 5 (for those subjects who 
complete the study but do not enter the extension study) except redraws for laboratory 
abnormalities present at Week 4 and urine pregnancy tests in female subjects. The laboratory 
determinations listed below will be obtained according to the visit schedule listed in the 
Schedule of Activities:
Blood Chemistry

Sodium;

Potassium;

Calcium;

Chloride;

Glucose (fasting);*


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
Bicarbonate or carbon dioxide;

Blood urea nitrogen or Urea;

Creatinine;

Creatine phosphokinase (CPK);

Phosphorus;

Magnesium;

Uric acid;

Bilirubin, total;

Bilirubin, direct;

Bilirubin, indirect;

Total protein;

Albumin;

Aspartate aminotransferase (AST);

Alanine aminotransferase (ALT);

lactate dehydrogenase (LDH);

Gamma-glutamyl transpeptidase (γGT);

Alkaline phosphatase.
Hematology

Hemoglobin;

Hematocrit;

Red blood cell count;

White blood cell count with differential [% and absolute];

Platelet count.
Urinalysis (Routine)

Specific gravity;


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
pH;

Dipstick Protein, qualitative; 

Glucose/sugar, qualitative;

Ketones/acetone, qualitative;

Hemoglobin/blood, qualitative;

Microscopic if blood or protein results are trace, +1, +2, +3, or +4.
Hormones

Free T4;

TSH;

Prolactin.
Lipid Profile

Triglycerides (fasting);*

Total cholesterol (fasting);*

High-density lipoprotein and low-density lipoprotein cholesterol (fasting);*

Insulin (fasting);*

HbA1c (fasting);*

Hepatitis serology.
*Subjects should remain fasting for at least 8 hours prior to these lab samples (glucose, lipid 
profile, insulin and HbA1c) being drawn.
Urine Pregnancy Test

For female subjects, a urine pregnancy test should be performed at all study visits, 
followed by a serum pregnancy test if the urine test is positive. 
Out-of-range values will be interpreted by the investigator with a comment of “not clinically 
significant” (NCS) or “clinically significant” (CS) on the final laboratory reports.  All 
laboratory tests with values that become abnormal to a clinically significant degree after 
investigational product administration must be repeated and the investigator must continue to 
follow-up as medically indicated until values have returned to baseline or until the condition
stabilizes.  If laboratory values do not return to normal or baseline within a reasonable 
period, the etiology must be identified and the sponsor notified.  All clinically significant 
laboratory tests will be recorded on the AE CRF.


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7.2.1.1. Total Volume of Blood Collected
The total volume of blood collected from each subject over the entire duration of the study 
will be approximately 70 mL. 
7.2.2. Urine Drug Screen
A urine drug screen (UDS) will be obtained according to the visit schedule listed in the 
Schedule of Activities.  In addition to the scheduled tests, a UDS may also be administered at 
any other visit that the investigator deems necessary.
Subjects with a positive test result for amphetamines, barbiturates, benzodiazepines, 
cannabinoids, opiates, and propoxyphene, at the discretion of the investigator and after 
discussion with the sponsor, may be eligible for admission if there is an acceptable medical 
explanation for the subject’s positive test result (ie, prior legitimate prescription of a 
benzodiazepine for anxiety or opiate for pain) or evidence of isolated abuse rather than a 
pattern of established drug use.
A positive urine drug screen after randomization should be discussed between the 
investigator and the sponsor as to the potential impact and continued participation of the 
subject in the study.
The following analytes will be tested:

Amphetamines;

Barbiturates;

Benzodiazepines;

Cannabinoids;

Cocaine;

Methadone;

Methaqualone;

Opiates;

Phencyclidine;

Propoxyphene.


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7.2.3. Full Physical Examination
A full physical examination including oral/tympanic body temperature (°C) will be 
conducted according to the Schedule of Activities.  The full physical examination will 
evaluate clinically important abnormalities within a body system (eg, general appearance, 
skin, head/ears/eyes/nose/throat, heart, lungs, breasts (if medically indicated), abdomen, 
external genitalia (if medically indicated), extremities, back/spinal system, lymph nodes) or 
worsening of medical history conditions.
Clinically important physical examination abnormalities detected at the screening visit 
should be noted on source documents and the medical history.  Thereafter, any new clinically 
important abnormalities or worsening of conditions noted at the screening visit must be 
recorded on source documents and recorded on the AE record as appropriate.
7.2.4. Body Weight, Height, BMI, BMI z-score, and Waist Circumference
Body weight (lbs/kg), height (inches/cm) and waist circumference (inches or cm) will be 
measured according to the Schedule of Activities.  All measurements should be taken with 
the subject wearing only light indoor clothing and without shoes.  Height will be measured 
with a stadiometer; weight will be measured with a standard physician’s scale.  Body Mass 
Index (BMI) and BMI z-score will be calculated from height and weight.  At screening, BMI
z-score is used to determine eligibility. 
BMI z-scores will be used to evaluate changes in body weight.  An increase in the BMI 
z-score (adjusted for age) of 1 or more is to be documented as an adverse event.  All BMI 
and BMI z-scores are to be recorded in the source documents. 
7.2.5. Blood Pressure/Pulse (Sitting and Standing)
Blood pressure (mm Hg) should be measured using a manual aneroid or mercury 
sphygmomanometer with a cuff appropriate to the subject’s arm girth placed over the bare 
skin. Subjects should rest sitting with feet flat on the floor at least 5 minutes before sitting 
blood pressure readings are taken.  The sitting pulse rate (beats/minute) should be measured 
after the blood pressure.  Pulse rate should be measured for at least 30 seconds.
After standing for approximately 2 minutes, another blood pressure reading will be taken 
followed by a standing pulse reading. 
Whenever possible, the subject should refrain from products containing nicotine or caffeine 
2 hours before taking blood pressure measurements.  Also, whenever possible, blood 
pressure measurements should be taken on the same arm throughout the study.
Blood pressure and pulse will be measured according to the Schedule of Activities.  At 
Visit 6/Week 4, subjects will take their morning study medication during the visit.  Blood 
pressure and pulse will be measured before study medication dosing (trough).


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7.2.6. 12-lead Electrocardiogram (ECG)
A 12-lead ECG will be conducted at various time points according to the Schedule of 
Activities.
Readings and interpretations of ECG tracings will be performed centrally.  Information to be 
reported by the central scoring site will include the subject’s demographic information; beats 
per minute (bpm); overall interpretation; rhythm type; respiratory rate; heart rate intervals 
PR, QRS, QT, QTcF (ms), and QTcB (ms); and any comments.  The values of QTcF will be 
used for clinical decision making and interpretative assessment of changes in QTc.  QTcB 
will be measured to enable comparisons with historical data but not used for clinical 
decisions due to inaccuracies of the Bazett’s formula in correcting for heart rate.
All ECGs must be obtained before or at least 3 hours after food intake.  ECGs must be 
obtained prior to blood pressure/pulse measurements and prior to collection of any 
blood sample
 because these assessments can affect the ECG.  To 
standardize the collection procedure, the ECG should be collected in a comfortable and quiet 
place after the subject has been allowed to rest in a supine position for approximately 
5 minutes.
Baseline and Visit 6 (end of treatment/early termination) ECGs must be administered in 
triplicate, tracings should be collected approximately 2 minutes apart.
At the Day 29/Week 4 visit, subjects will take their morning medication with food at the 
visit.  An ECG will be done before dosing.
All ECGs must be reviewed for safety (including a review of the QTcF value) at the site by a 
physician within a reasonable time from the day of the recording [48 hours is recommended], 
signed and dated by the reviewing physician and retained in the subject’s study records.
Participation in the study is contingent on the subject having both screening and baseline 
ECGs without clinically significant abnormalities. 
ECGs showing a QTcF of ≥480 msec or a suspected increase of QTcF from baseline of 
60 msec or greater must be repeated within the same visit.  If the QTcF value persists at 
≥480 msec and/or the change from baseline persists at ≥60 msec, the study drug must be 
discontinued immediately and a pediatric cardiologist or an adult cardiologist experienced in 
the interpretation of pediatric ECGs should be contacted to discuss the ECG result (see 
Section 6.7.1).
If discontinued, the subject will not be eligible to enter the open-label extension trial.
7.2.7. Child Depression Rating Scale – Revised (CDRS-R)
The Child Depression Rating Scale – Revised17 (CDRS-R) is a clinician-rated scale that 
assesses 17 distinct symptom areas to derive an index of depression severity.  Though 
originally developed for children 6-12 yrs, it has been widely used with adolescents and its 
developers recommend it for both children and adolescents.18 Clinicians’ ratings are based 
on information obtained from interviews with both child and parent (or guardian) informants; 
CCI


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interview guides have been developed to structure the interview to ensure all 17 symptom 
areas are assessed.  For this trial, the manual’s recommendations on resolving discrepancies 
between informants will be used (ie, most impaired rating given by valid informant will be 
assigned).  It takes about 20-30 min to administer and rate the CDRS-R.  Ratings are 
assigned on a 7-point scale (ranging from 1-7, with higher values indicating greater 
impairment).  A total scale score is calculated by summing the 17 items.  The total score on 
the CDRS-R will be used to assess changes in depression severity over time between 
treatment groups. 
7.2.8. Movement Disorder Scales
The following scales will be used to assess symptoms and findings related to Parkinsonism, 
akathisia, and abnormal involuntary movements.  Investigators will be instructed to record 
movement disorders as adverse events (AEs) only if they are clinically meaningful.  
Specifically, investigators will be asked to record the disorder as an adverse event only if 
(1) clinically meaningful movement disorder side effects are observed or are volunteered by 
the subject, (2) a clinically meaningful movement disorder is present at baseline and 
increases in severity, or (3) concomitant therapy (benztropine, benzhexol, or other 
anticholinergics or propranolol) is initiated or reinstated for movement disorders while the 
subject is participating in the study.  All dystonic movements are to be recorded as AEs 
unless present at the same severity at baseline. 
7.2.8.1. Simpson-Angus Rating Scale (SARS)
The Simpson-Angus Rating Scale19 (SARS) will be administered to assess parkinsonian 
symptoms and related extrapyramidal side effects through observation of the subject.  The 
scale contains 10 items, including gait, arm dropping, shoulder shaking, elbow rigidity, wrist 
rigidity, leg pendulousness, glabellar tap, tremor, and salivation.  The head rotation item 
(from the modified Simpson-Angus Rating Scale) will be substituted for the original #7 item, 
head dropping.  Seven of the ten items measure parkinsonian rigidity.  Each item is rated on 
an anchored 5-point scale, with 0 = the absence of the condition or normal and 4 = the most 
extreme form of the condition.  A total score is obtained by adding all of the scores of the 
individual items.  The SARS takes approximately 10 minutes to administer.
7.2.8.2. Barnes Akathisia Rating Scale (BAS)
The Barnes Akathisia Rating Scale20 (BAS) will be administered to assess akathisia.  The 
scale is designed to rate akathisia through observation of restless behavior and questioning of 
the subject to determine the degree of subjective restlessness and distress associated with 
restlessness.  A global clinical rating completes the assessment.
The first 3 items of the BAS (Objective, Subjective, and Distress related to restlessness) are 
rated on a 4-point scale (0-3).  The fourth item, the global clinical assessment of akathisia, 
uses a 6-point scale (0-5).  Only the global clinical assessment measure from this scale will 
be analyzed.  Higher scores indicate increased severity. All ratings are anchored. The BAS 
takes approximately 10 minutes to administer.


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7.2.8.3. Abnormal Involuntary Movement Scale (AIMS)
The Abnormal Involuntary Movement Scale21 (AIMS) will be used to document occurrences 
of dyskinesias in subjects, specifically tardive dyskinesia.  The scale incorporates observation 
and brief examination of the subject and consists of 12 items.  Items 1-4 assess the severity of 
orofacial movements.  Items 5-7 assess extremity and truncal dyskinesias.  Items 8-10 rate 
global severity of movements as indicated by the examiner’s judgment of the severity of 
abnormal movements (item 8), the examiner’s judgment of the subject’s incapacitation due to 
the movements (item 9), and the subject’s awareness of the movements and associated 
distress (item 10).  Items 11-12 concern the subject’s dental status.
Items 1-10 are rated on a 5 point (0-4) anchored severity scale with 0 = none, 1 = minimal, 
may be normal, 2 = mild, 3 = moderate, and 4 = severe.  Items 11 and 12 are questions with 
yes/no answers.  Only the sum of the first 7 items will be analyzed.  The AIMS can be 
completed in 5-10 minutes.
7.2.9. Suicidality Assessments
7.2.9.1. Suicidality Assessments at Screening
A risk assessment should be done if the subject’s responses on any of the screening 
instruments or other screening information indicate that:

The subject has had suicide ideation associated with actual intent and/or plan at any 
time in their lifetime such that a positive response (‘Yes’) is made on items 4 or 5 of 
the suicidal ideation subscale of the C-SSRS; or

The subject has any lifetime history of suicide behaviors such that a determination of 
‘yes’ is made to any of the suicide behavior items of the C-SSRS; or

In the investigator’s judgment a risk assessment is required. 
A written copy of the risk assessment should be included in the subject’s clinical record 
(source documentation). 
7.2.9.2. Suicidality Assessments at Baseline and Post-baseline Visits
At the baseline visit (visit 2) and post-baseline visits, the C-SSRS will be administered.  If 
there are ‘yes’ answers on items 4 or 5 of the suicidal ideation subscale of the C-SSRS or any 
behavioral questions of the C-SSRS, a risk assessment should be done to determine whether 
it is safe for the subject to continue to participate in the trial.  If there are any ‘yes’ answers 
on items 4 or 5 of the suicidal ideation subscale of the C-SSRS or any behavioral questions 
of the C-SSRS at the post-baseline visits, supplemental information should be collected and 
the appropriate CRFs completed for the purpose of constructing a narrative that allows a 
detailed description of the adverse event(s) and outcome(s).  Supplemental information will 
also be collected for a completed suicide.
A written copy of the risk assessment should be included in the subject’s clinical record 
(source documentation). 


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7.2.9.3. Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS)22 will be used to evaluate suicide 
ideation and severity at screening, baseline, and each post-baseline visit.  The C-SSRS is a 
semi-structured interview that captures the occurrence, severity, and frequency of 
suicide-related thoughts and behaviors during the assessment period.  The interview includes 
definitions and suggested questions to solicit the type of information needed to determine if a 
suicide-related thought or behavior occurred.  The C-SSRS is the prospective counterpart to 
the Columbia Classification Algorithm of Suicide Assessment (C-CASA) categorization 
system.23  Responses to individual C-SSRS items can be mapped directly to the C-CASA 
categories (ie, completed suicide, attempted suicide, preparatory acts, suicidal ideation, 
non-suicidal self-injurious behavior) for summary and analysis purposes.  The C-SSRS has 
been broadly used in numerous industry sponsored randomized clinical trials (RCTs) in both 
CNS and non-CNS indications.
The C-SSRS is available in a Baseline version and a “Since Last Visit” version.  The baseline 
version assesses suicidal behavior over the lifetime and suicidal ideation at the time the 
subject was most suicidal.  The “Since Last Visit” version assesses suicidal ideation and 
behavior between visits in a clinical trial.  The clinician administering the interview should 
use information provided by the subject as well as other sources of information (eg, from 
parent(s) or guardian(s)) to determine if suicidal ideation or behavior occurred. 
The C-SSRS contains 2 required items pertaining to suicidal ideation, 4 required items 
pertaining to suicidal behavior, and 1 required item pertaining to non-suicidal self-injurious 
behavior.  There are 8 additional suicidal ideation items and 2 additional suicidal behavior 
items which are completed in cases of positive responses for other items, as well as 2 items 
for completed suicide and suicide behavior present during the interview.  Thus, there is a 
maximum of 19 completed items.
The Suicidal Ideation items are rated on a dichotomous scale (yes or no).  There is also an 
Intensity of Ideation subscale, which assesses the Frequency, Duration, Controllability, 
Deterrents, and Reasons for Ideation associated with the Most Severe suicide ideation 
reported by the patient, using 5-point Likert scales.  The Suicidal Behavior items and the 
Non-Suicidal Self-Injurious Behavior items are also scored dichotomously yes or no.  In 
addition, the total number of attempts (including interrupted and aborted attempts) is 
recorded.  This is followed by a Lethality subscale which rates the Actual Lethality/Medical 
Damage and Potential Lethality of the attempt on 5- and 3-point Likert scales, respectively.  
A total score can be generated for the Intensity of Ideation portion of the interview.  
Otherwise, no other total scores are generated.  In the event of a positive categorical response 
the interviewer can provide text or narrative that further describes the thought or behavior.
For subjects who are ages 7-11 at the Screening Visit, the Children’s Since Last Visit version 
of the C-SSRS should be utilized, even if the child has his/her 12th birthday during 
participation in this study.  The Since Last Visit version refers to the subject’s experience 
since their last visit.


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For subjects who are ages 12-17 at the Screening Visit, the Since Last Visit version of the 
C-SSRS should be utilized.  The Since Last Visit version refers to the subject’s experience 
since their last visit. 
7.2.10. Subject Contact
Contact should be made with the subject by the investigator or designated staff member, 
either by telephone or in person as an unscheduled visit, after the baseline visit but before 
Visit 3 and after Visit 3 but before Visit 4 to ensure that the subject is taking the proper 
capsules at the proper time and to monitor the tolerability, safety, and efficacy of the titration 
plan/study drug.
7.3. Efficacy Assessments
7.3.1. Young Mania Rating Scale (YMRS)
The YMRS is an 11-item instrument used to assess the severity of mania in patients with a 
diagnosis of bipolar disorder. The 11 items are: Elevated Mood, Increased Motor Activity 
Energy, Sexual Interest, Sleep, Irritability, Speech (Rate and Amount), Language - Thought 
Disorder, Content, Disruptive - Aggressive Behaviour, Appearance, and Insight.  It has 
operationally-defined anchors, and is based on patient self-report combined with clinician 
observations.  The YMRS will be administered using the Kowatch interview guide, which 
adapts the scale for pediatric populations.  It requires 15-30 minutes to complete.  The 
YMRS was developed for the assessment of mania severity in hospitalized adults, but its 
validity in pre-pubertal patients has been demonstrated, and it is now widely accepted and 
used as a primary measure of mania severity in outpatient studies of children and adolescents 
with bipolar disorder.24,25
The YMRS must be administered by an appropriately qualified and experienced individual 
who has completed the Pfizer rater training program.  For each subject, the same rater should 
administer the YMRS at each of the indicated timepoints.  A co-rater who has successfully 
completed the Pfizer rater training program may administer the YMRS in lieu of the primary 
rater, on rare occasions when the primary rater is unavailable due to illness or other 
unavoidable circumstances.
7.3.2. Clinical Global Impression Scales (CGI-S and CGI-I)
The Clinical Global Impression (CGI) Scale26 is a standardized assessment tool used to rate 
the severity of a subject’s illness and improvement over time.  The CGI using two subscales: 
Severity of Illness (CGI-S) and Global Improvement (CGI-I).  The CGI-S assesses the rater’s 
impression of the subject’s current illness state.  Scores range from 1 (not ill at all) to
7 (among the most extremely ill).  The CGI-I subscale rates the subject’s improvement or 
worsening from baseline.  Scores range from 1 (very much improved) to 7 (very much 
worse). 










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Condition
Action
Syncope
All syncopal episodes suggestive of cardiac arrhythmia (sudden loss of 
consciousness, loss of postural tone, and no pre-syncopal phase), except 
vasovagal syncope will be considered adverse events and the subject will 
be discontinued from the study.  Every effort should be made to obtain 
vital signs and an electrocardiogram at the time of the event.  Further 
evaluation, eg, Holter monitoring, may also be useful.  Subjects 
experiencing syncope of probable vasovagal origin (onset not sudden but 
preceded by a pre-syncopal phase, presence of predisposing factors such 
as blood sampling procedure, standing, hot shower, hair curling, etc) will 
also be considered adverse events but subjects may continue study 
participation after sponsor approval.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For AE’s and SAEs, the active reporting period to Pfizer or its designated representative 
begins from the time that the subject provides informed consent, which is obtained prior to 
the subject’s participation in the study, ie, prior to undergoing any study-related procedure 
and/or receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  Serious adverse events occurring to a subject 
after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all serious adverse events that the 
investigator believes have at least a reasonable possibility of being related to study drug are 
to be reported to the Sponsor.


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
AEs (serious and non serious) should be recorded on the CRF from the time the 
subject has provided informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study related procedure and/or 
receiving investigational product, through and including 28 calendar days after the 
last administration of the investigational product.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.


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8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate. In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;


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
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section on SAE Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).


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
Concurrent with:

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least one time the 
upper limit of normal or if the value reaches ≥3 times the upper limit of normal 
(whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment. In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time
(PT)/ international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for Liver function test (LFT) abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).


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Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE case report forms (CRFs), the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the AE.  For 
purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.


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8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see Section on Reporting Requirements).  If the
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy -occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.
2. An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
3. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event Report Form and an 
EDP Supplemental Form, regardless of whether an SAE has occurred.  In addition, the 
investigator must submit information regarding environmental exposure to a Pfizer product 
in a pregnant woman (eg, a subject reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) using the EDP Supplemental Form.  This must be 
done irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).


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Follow-up is conducted to obtain general information on pregnancy and its outcome for all 
EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow up 
to the initial EDP Supplemental Form.  In the case of a live birth, the structural integrity of 
the neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) 
for termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner. The Investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also Section 6.7 Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 


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When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/parent/legal guardian.  In addition, each study subject/parent/legal guardian 
will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding, and occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.


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8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
9.1. Sample Size Determination
This study has been designed to have 85% statistical power to show a difference between 
drug and placebo at conventional levels (ie, 5% level, 2-sided) of statistical significance. 
Based on the previous Pfizer pediatric study A1281132, the estimated difference in change 
from baseline of the YMRS total score for ziprasidone versus placebo is –4.55 points (from 
descriptive and LSMEANs at week 4) with an approximate within-group standard deviation 
of 8.0.
The effect size used in the design of this study is 0.57, and is consistent with the weighted 
estimate of the effect size (0.65) of second generation antipsychotics in pediatric bipolar 
patients published in the recent meta-analysis of Correll et al,28 which was based on the 
results of multiple placebo-controlled trials.
Using EAST (version 5.4) for a two-sample t-test, the sample size needed to detect this 
difference with 85% power at a two-sided significance level of 5% was determined to be
111 randomized subjects.  Adjusting for dropouts (approximately 38% at week 4) and 
including the additional 14 subjects being enrolled to mitigate the impact of the rater training 
issue, the total sample necessary is 194 subjects (1:1 enrollment with 97 on ziprasidone and 
97 on placebo).  The power for this study has now increased to 88%.
The randomization will be stratified by weight group (weight <45 kg, weight ≥45 kg) to 
ensure treatment balance within each of the two weight groups.
Shortly after enrollment into this study commenced, Pfizer was informed by the rater training 
vendor (on 29 September 2014) that an internal audit had revealed an error in their internal 
processes. This error resulted in some sites being notified that they could start screening 
subjects before all raters at the sites had completed all of the required rater training activities. 
The primary endpoint assessments (YMRS) and/or the diagnostic interviews (KSADS) of 
14 subjects were impacted by the rater training issue.
In agreement with the FDA to ensure the robustness of the inferential analysis, Pfizer will 
recruit an additional 14 subjects into the study and conduct a sensitivity analysis excluding 
these 14 patients to mitigate the possible effect of the rater training issue that was identified.
The original sample size for this study was 180 subjects. For the revised sample size, a total 
of 194 subjects (97 ziprasidone: 97 placebo) will be recruited from approximately 
60-70 worldwide sites.  The power of the study including the additional subjects is 88%. It is 
estimated that approximately 300 subjects will be required to be screened to achieve this 
enrollment target with an anticipated screen failure rate of approximately 40%.


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9.2. Statistical Summary and Analysis
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP), which will be finalized and dated 
prior to enrolling the first subject, and subsequently maintained by the sponsor.  The SAP 
may modify the plans outlined in the protocol; however, any major modifications or 
significant change to the primary endpoint definition and/or its or analysis will also be 
reflected in a protocol amendment.
9.3. Definition of Study Populations
For this protocol, an intent-to-treat (ITT) analysis set will be defined as the set of all subjects
who were randomized, had baseline measurements, took at least 1 dose of study medication 
(ziprasidone or placebo), and with at least 1 post-baseline visit. 
The per-protocol (PP) analysis set will include all patients in the ITT set without major 
protocol violations considered to impact the interpretation of the primary efficacy endpoint.  
Protocol deviations will be reviewed to generate the list of subjects with significant 
deviations to be excluded from the PP analysis set.  The PP exclusion criteria will be 
finalized prior to breaking the blind.
Both the ITT and PP analysis sets will be used in the analyses of all efficacy endpoints, with 
the ITT being primary.  The Safety Analysis Set which includes all subjects who were 
randomized and took at least 1 dose of study medication (ziprasidone or placebo) will be 
used in the analyses of the safety data.  Only the ITT analysis set will be used in the analyses 
of the outcome 
 and special safety assessments (CSSRS data, CDRS, and movement 
disorder scales).
9.4. Study Conduct and Subject Disposition
The number of subjects screened, randomized to the double-blind treatment phase, and 
completing the study will be summarized.  The reason for all discontinuations will be 
summarized by treatment group.
9.5. Baseline Characteristics and Treatment Group Comparability
Baseline demographic and other characteristics will be tabulated for all treated subjects.  
Quantitative variables will be described by standard descriptive statistics (mean, standard 
deviation, minimum, and maximum), and qualitative variables will be summarized by 
frequency tables.
9.6. Efficacy Analysis 
Early termination (ET) visit efficacy data will be “windowed” (ie, “slotted” to a regular study 
visit time using an algorithm specified in the SAP. 
Descriptive statistics for all efficacy endpoints by treatment group and visit will be provided.
CCI


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9.6.1. Analysis of Primary Endpoint
The primary efficacy endpoint is change from baseline in the YMRS score.  The primary 
time point is Week 4.  All other collection time points will be considered secondary.
Analysis of change from baseline in the YMRS score will be conducted using Statistical 
Analysis System (SAS) PROC MIXED to fit a mixed model repeated measures analysis of 
covariance (ANCOVA) with treatment, visit and visit-by-treatment interaction, and weight 
category as fixed effects and baseline score as a covariate.  Subject effect will enter the 
MMRM model as a random effect.  The estimation method used will be restricted maximum 
likelihood.  An unstructured covariance matrix will be used in the REPEATED statement.  In 
case SAS PROC MIXED fails to converge, other covariance matrix structures will be 
considered in the sequence of Toeplitz, First-Order Autoregressive, and Variance 
Components.  The EMPIRICAL option will be specified to compute the estimated 
variance-covariance matrix of the fixed-effects parameters.  Type III sums of squares will be 
used to test both main effects and interactions.  The primary comparison will be between 
ziprasidone and placebo at Week 4, conducted as a two-sided test at 5% level of significance.  
Based on the specified model, the point estimate and 95% confidence interval (CI) for the 
difference in means between the two treatments will be constructed using the least squares 
means and appropriate standard errors.
If the test result is significant and in favor of ziprasidone, then efficacy of flexibly-dosed oral 
ziprasidone in the treatment of children and adolescents with Bipolar I Disorder (current or 
most recent episode manic) will be established.
A sensitivity analysis will be done by adding an interaction term of treatment and weight 
category to the primary analysis model specified above.  Supplemental analyses of the 
primary variable will be performed to support the robustness of the conclusions drawn from 
the primary mixed models repeated measures analysis described above. These supplemental 
analyses will include the following:

Summaries of reasons for discontinuations by treatment group;

Pattern-mixture ANCOVA analysis of change from baseline YMRS scores.
For the pattern-mixture analysis, grouping of the subjects on the basis of their dropout or 
missing-data patterns will be explored.  Two appropriate grouping variables will be defined 
in the SAP.  The percentage of subjects showing a 50% reduction in YMRS scores from 
baseline to Week 4 will be presented descriptively for each group.
9.6.2. Analysis of Secondary Endpoints
The secondary efficacy endpoints include:

Change from baseline to week 4 in the CGI-S score (key secondary endpoint);

Change from baseline to weeks 1, 2, and 3 in YMRS and CGI-S;










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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be [password protected or secured in a locked room to prevent access by unauthorized third 
parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer. To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, 
the investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs data collection tools ([/DCTs)] and hospital 
records), all original signed informed consent[/assent] documents, copies of all 
CRFs[/DCTs], safety reporting forms, source documents, detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (eg, letters, meeting 


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minutes, and telephone call reports).  The records should be retained by the investigator 
according to the ICH guidelines, according to local regulations, or as specified in the clinical 
study agreement (CSA), whichever is longer.  The investigator must ensure that the records 
continue to be stored securely for so long as they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 


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The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be [password protected or secured in a locked room] to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent/assent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent[/assent] documents used during the informed consent process and any 
subject recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection.
The investigator must ensure that each study subject, [or his or her legally acceptable 
representative, or parent(s) or legal guardian if a minor,] is fully informed about the nature 
and objectives of the study, the sharing of data relating to the study and possible risks 
associated with participation, including the risks associated with the processing of the 
subject’s personal data.  The investigator further must ensure that each study subject, [or his 
or her legally acceptable representative, or parent(s) or legal guardian if a minor,] is fully 
informed about his or her right to access and correct his or her personal data and to withdraw 
consent for the processing of his or her personal data.
If the study permits consent from a legally acceptable representative, include the following 
paragraph: 
Whenever consent is obtained from a subject’s [legally acceptable representative/parent(s) or 
legal guardian], the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited that he or she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide 
his or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 


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person signing the consent was the subject’s legally acceptable representative, the consent 
signer’s relationship to the study subject (eg, parent, spouse), and that the subject’s assent 
was obtained or waived.  If assent is obtained verbally, it must be documented in the source 
documents.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must reconsent as adults to remain in the study.  If the 
enrollment of emancipated minors is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject [or the subject's legally acceptable representative, parent(s), or 
legal guardian and the subject’s assent, when applicable, before any study specific activity is 
performed [unless a waiver of informed consent has been granted by an IRB/EC].  The 
investigator will retain the original of each subject's signed consent[/assent] document.
12.4. Subject Recruitment
Advertisements approved by ethics committees and/investigator databases may be used as 
recruitment procedures.  All advertisements, however, should be reviewed by the Sponsor 
before seeking ethics or IRB approval.
As part of the study recruitment plan, the following strategies may also be initiated (where 
necessary, the appropriate ethics committee and/or IRB approvals must be obtained before 
implementing): specialist site referrals; indication area support group visits; web-based links; 
community postings; and hospital newsletters.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as the time when the last subject 
completes the last visit.


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of ziprasidone at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 30 days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.


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www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed. If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the study results themselves) before disclosure.
If the study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1.
Lish JD, Dime-Meenan S, Whybrow PC, Price RA, Hirschfeld RM. The National 
Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J 
Affective Disord. 1994;31(4):281-94.
2.
Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL, Delbello MP, Soutullo 
CA. Diagnostic characteristics of 93 cases of a prepubertal and early adolescent bipolar 
disorder phenotype by gender, puberty and comorbid attention deficit hyperactivity 
disorder. J Child Adolesc Psychopharmacol. 2000a;10(3):157-64.
3.
Geller B, Bolhofner K, Craney JL, Williams M, DelBello MP, Gundersen K. 
Psychosocial functioning in a prepubertal and early adolescent bipolar disorder 
phenotype. J Amer Acad Child Adolesc Psychiatr. 2000b;3:1543-8.
4.
McClellan J, Kowatch R, Findling RL. Practice parameter for the assessment and 
treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc 
Psychiatry. 2007; 46:107-125.
5.
Kowatch RA, Fristad M, Birmaher B, Wagner KD, Findling RL, Hellander M, and the 
Child Psychiatric Workgroup on Bipolar Disorder. Treatment guidelines for children 
and adolescents with Bipolar Disorder. J Am Acad Child Adolesc Psychiatr. 
2005;44:213-235.
6.
Nandagopal JJ, DelBello MP and Kowatch R.  Pharmacologic Treatment of Pediatric 
Bipolar Disorder. Child Adolesc Psychiatr Clin N Am. 2009: 455-469.
7.
Correll CU. Weight gain and metabolic effects of mood stabilizers and antipsychotics in 
pediatric bipolar disorder: a systematic review and pooled analysis of short-term trials. J 
Am Acad Child Adolesc Psychiatry. 2007; 46:687-700.
8.
Patel NC, Keck PE, Jr. Ziprasidone: efficacy and safety in patients with bipolar
disorder. Expert Rev Neurother. 2006; 6:1129-1138.
9.
Beedham C, Miceli JJ, Obach RS (2003) Ziprasidone metabolism, aldehyde oxidase, 
and clinical implications. J Clin Psychopharmacol 23:229-232.
10.
Investigator’s Brochure for Ziprasidone, June 2013.
11.
McClellan J, Kowatch R, Findling RL, et al. Practice Parameter for the Assessment and 
Treatment of Children and Adolescents with Bipolar Disorder. J Am Acad Child 
Adolesc Psychiatry, 46:1, January 2007.
12.
Haas M, DelBello MP, Pandino G, et al. Risperidone for the treatment of acute mania in 
children and adolescents with bipolar disorder: a randomized, double-blind, 
placebo-controlled study. Bipolar Disorder. 2009; 11(7):687-700.


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13.
Tohen M, Kryzhanovskaya L, Carlson G, et al. Olanzapine versus placebo in the 
treatment of adolescents with bipolar mania. Am J Psychiatry 2007; 164:1547-1556.
14.
Findling RL, Nyilas M, Forbes RA, et al. Acute treatment of pediatric bipolar I disorder, 
manic or mixed episode, with aripiprazole: A randomized, double-blind, 
placebo-controlled study. J Clin Psychiatry 2009; 70(10):1441-1451.
15.
Information on the pediatric bipolar development programs for Zyprexa (olanzapine), 
Seroquel (quetiapine) and Geodon (ziprasidone) is available at the website for the June 
9-10 meeting of the FDA Psychopharmacologic Drugs Advisory Committee at the 
following link: 
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Psychop
harmacologicDrugsAdvisoryCommittee/ucm126199.htm.
16.
Kafantaris V, Coletti DJ, Dicker R, et al. Lithium treatment of acute mania in 
adolescents: A placebo-controlled discontinuation study. J Am Acad Child Adolesc 
Psychiatry, 2004; 43(8):984-993.
17.
Poznanski EO, Freemen LN, & Mokros HB. (1985). Children’s Depression Rating 
Scale-Revised. Psychopharmacol Bull, 21, 979-989.
18.
Poznanski EO & Mokros HB. (1996). Children’s Depression Rating Scale, Revised, 
Manual. LA: Western Psychological Services.
19.
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand, 1970;212:11-19.
20.
Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154: 
672-676.
21.
Guy W. ECDEU Assessment Manual for Psychopharmacology–Revised: United States
1976. Rockville, Maryland: United States Department of Health, Education, and 
Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration, NIMH Psychopharmacology Research Branch, Division of Extramural 
Research Programs, 1976; DHEW Publication Number (ADM)76-338. 534-537.
22.
Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, Fisher P, Zelazny J, Burke 
A, Oquendo M, Mann, J. Coloumbia-Suicide Severity Rating Scale,  Version 
7/19/2008; New York State Psychiatric Institute, 1051 Riverside Drive, NY, NY; for 
inquiries contact Kelly Posner at posnerk@childpsych.columbia.edu.
23.
Posner K, Oquendo M, Gould M, Stanley B, Davies M.  Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): Classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants.  Am J Psychiatry. 
2007;165:1035-43.


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24.
Fristad MA, Weller RA, Weller EB. The Mania Rating Scale (MRS): further reliability 
and validity studies with children. Ann Clin Psychiatr. 1995;7:127-32.
25.
DelBello MP, Schwiers ML, Rosenberg HL, Strakowski SM. A double-blind, 
randomized, placebo-controlled study of quetiapine as adjunctive treatment for 
adolescent mania. J Am Acad Child Adolesc Psychiatry. 2002;41:1216-1223.
26.
Guy W. ECDEU Assessment Manual for Psychopharmacology – Revised: United States 
– 1976. Rockville, Maryland: United States Department of Health, Education, and 
Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration, NIMH Psychopharmacology Research Branch, Division of Extramural 
Research Programs, 1976; DHEW Publication Number (ADM)76-338. 218-222.
27.
Shaffer D, Gould MS, Brasic J, et al. A Children's Global Assessment Scale (CGAS). 
Arch Gen Psychiatr. 1983; 40(11):1228-31.
28.
Correll et al, Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and 
adult patients with bipolar I mania: a comparative analysis of acute, randomized, 
placebo-controlled trials. Bipolar Disorders 2010: 12: 116-141.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AACAP
American Academy of Child and Adolescent Psychiatry
AE
Adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
ASD
Isolated atrial septal defect
AST
aspartate aminotransferase
BA(R)S
Behavioural Activity Rating Scale
BID
Twice daily
BMI
Body Mass Index
BP
Blood Pressure
bpm
beats per minute
C-CASA
Columbia Classification Algorithm of Suicide Assessment
CDC
Centers for disease control
CDRS-R
Child Depression Rating Scale - Revised
CDS
Core Data Sheet
CGIC
Clinical Global Impression of Change
CGI-I
Clinical Global Impression of Improvement 
CGI-S
Clinical Global Impression of Severity
CI
confidence interval
CIDI
Composite International Diagnostic Interview
CIOMS
Council for International Organizations of Medical Sciences
CNS
central nervous system
CPBAQ
Children's Problem Behavior and Aggression Questionnaire
CPK
Creatine phosphokinase
CRF
case report form
CRO
Contract Research Organization
CS
clinically significant
CSA
Clinical Study Agreement
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP3A4
cytochrome P4503A4
DCTs
data collection tools
DHEA
dehydroepiandrosterone
DIS
Diagnostic Interview Schedule
DSM
Diagnostic and Statistical Manual of Mental Disorders
DSMB
Data Safety and Monitoring Board
EC
Ethics Committee
CCI
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Abbreviation
Term
ECG
electrocardiogram
E-DMC
External Data Monitoring Committee
EDP
Exposure during pregnancy
EPS
extrapyramidal symptoms
ESRS-A
Extrapyramidal Symptom Rating Scale-A
ET
Early termination
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HAM-D
Hamilton Depression Scale
HbA1c
glycosylated hemoglobin
HbsAg
hepatitis B virus surface antigen
hCG
human chorionic gonadotophin
HIV
Human Immunodeficiency Virus
5-HT1A
5-Hydroxytryptamine Receptor 1A
5-HT2A
5-Hydroxytryptamine Receptor 2A
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IM
intramuscular
INR
international normalized ratio
IQ
Intelligence Quotient
IRB
Institutional Review Board
ITT
Intent-to-Treat
IUD
intrauterine device
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
K-SADS
Kiddie Schedule for Affective Disorders and Schizophrenia
LDH
lactate dehydrogenase
LFT
Liver function test
LPD
Local Product Document
LSMEANs
Least-Squares Means
MADRS
Montgomery and Asberg Depression Rating Scale
MAO
monoamine oxidase
MedDRA
Medical Dictionary for Drug Regulatory Activities
MHP
mental health provider
MINI
Mini-international neuropsychiatric interview
MINI-KID
Mini International Neuropsychiatric Interview for Children and 
Adolescents
MMRM
mixed model repeated measures
MSW
Clinical Social Worker
NCS
not clinically significant


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Abbreviation
Term
NSAIDs
non-steroidal anti-inflammatory drugs
PCD
primary completion date
PDA
patent ductus arteriosus
PDD-NOS
pervasive developmental disorder – not otherwise specified
PI
principal investigator
PNP
psychiatric nurse practitioner
PP
Per-Protocol
PR
Pulse rate 
PREA
Pediatric Research Equity Act
PRN
pro re nata
PSRAEs
Possibly Suicide Related Adverse Events
PT
prothrombin time
QTc
QT corrected
QTcB
Bazett’s correction
QTcF
Fridericia correction
RCTs
randomized clinical trials
SAE
serious adverse event
SAP
statistical analysis plan
SA(R)S
Simpson-Angus Rating Scale
SAS
Statistical Analysis System
SCID
Structured Clinical Interview for DSM-IV
sNDA
Supplemental New Drug Application
SPC
Summary of Product Characteristics
SRSD
single reference safety document
SubI
Sub Investigator
TSH
thyroid-stimulating hormone
UDS
urine Drug Screen
ULN
upper limit of normal
UPDRS
Unified Parkinson's disease rating scale
US
United States
USPI
United States Package Insert
VSD
ventricular septal defect
YMRS
Young Mania Rating Scale
CC
I
CCI

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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Sample Size Determination.......................................................................................7
2.2.1. Re-estimation of Sample Size.......................................................................7
2.3. Study Objectives .......................................................................................................8
2.3.1. Primary Objectives .......................................................................................8
2.3.2. Secondary Objectives ...................................................................................8
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................9
4. HYPOTHESES AND DECISION RULES...........................................................................9
4.1. Statistical Hypotheses ...............................................................................................9
4.2. Statistical Decision Rules..........................................................................................9
5. ANALYSIS SETS ...............................................................................................................10
5.1. ITT Analysis Set......................................................................................................10
5.2. ‘Per Protocol’ Analysis Set .....................................................................................10
5.3. Safety Analysis Set..................................................................................................10
5.4. Treatment Misallocations........................................................................................10
5.5. Protocol Deviations.................................................................................................11
5.5.1. Deviations Assessed Prior to Randomization.............................................11
5.5.2. Deviations Assessed Post-Randomization..................................................11
6. ENDPOINTS AND COVARIATES ...................................................................................11
6.1. Efficacy Endpoint(s) ...............................................................................................11
6.1.1. Primary Efficacy Endpoint:........................................................................11
6.1.2. Key Secondary Efficacy Endpoint: ............................................................11
6.1.3. Secondary Endpoints:.................................................................................11
6.2. Safety Endpoints .....................................................................................................12
6.2.1. Safety Assessments.....................................................................................12
6.2.2. Special Safety Assessments........................................................................12
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2. INTRODUCTION
Ziprasidone is an atypical antipsychotic with a high affinity for the dopamine D2 receptor 
and the 5HT2A receptors. It blocks re-uptake of serotonin and norepinephrine and exhibits 
5HT1A agonist activity.  
The present study is designed to assess the efficacy, safety, and tolerability of oral 
ziprasidone in child and adolescent subjects with Bipolar I Disorder (current or most recent 
episode manic). It is designed to comply with a Pediatric Research Equity Act (PREA) 
commitment to assess the safety and effectiveness of Geodon® (ziprasidone) as a treatment 
for bipolar disorder in pediatric patients ages 10 to 17 (children and adolescents), issued by 
the US Food and Drug Administration (FDA) to Pfizer in August 2004.  
The overall goal of the study is to assess the safety profile and efficacy of ziprasidone in the 
treatment of pediatric mania in association with bipolar disorder, and to develop other 
relevant information, eg, 
 pertinent to evaluating the effects of 
ziprasidone in children and adolescents. The study population in this protocol will be limited 
to children and adolescents aged 10 to 17 years (inclusive). In this age range, the same 
DSM-V criteria for mania are employed for both the pediatric and adult population. While 
the lower end of the age range for bipolar disorder is not clear, it is both uncommon and 
difficult to make this diagnosis below the age of 10 years. On the other hand, bipolar 
disorder in the 10 to 17 year old population is thought to be relatively common and 
phenomenologically similar to bipolar disorder seen in adults.
2.1. Study Design
This will be a Phase 3, multicenter, 4-week, randomized, double-blind, placebo-controlled, 
parallel-group trial to evaluate the efficacy, safety, and tolerability of flexibly dosed 
ziprasidone compared with placebo for the treatment of Bipolar I Disorder (current or most 
recent episode manic) in children and adolescents aged 10 to 17 years (inclusive). 
Ziprasidone (or placebo) will be administered as oral capsules given twice daily (BID) with 
food.  Ziprasidone (or placebo) will be titrated over the first 7-14 days of treatment to the 
target dose range (60-80 mg/day for subjects <45 kg and 120-160 mg/day for subjects 
≥45 kg), after which stable dosing will be maintained, if possible, through the end of the 
double-blind treatment period (end of Week 4, Day 29).  However, depending on the clinical 
judgment of the investigator, the dose may be down titrated at any time in the case of 
tolerability or safety concerns.
Approximately 194 subjects (97 ziprasidone: 97 placebo) will be recruited from 
approximately 60 -70 worldwide sites.  It is estimated that approximately 300 subjects will be 
required to be screened.
The study will begin with a screening visit to determine subject eligibility, followed by a 
1-14 day period to allow for wash-out of exclusionary medications and the performance of 
two sequential pregnancy tests separated by a minimum interval of 14 days in all female 
subjects. Subjects who qualify will be randomized at baseline (Day 1) to receive either 
double-blind oral ziprasidone or placebo (randomization ratio 1:1). The randomization will 
be stratified by weight group (weight <45 kg, weight ≥45 kg).
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2.2. Sample Size Determination
This study has been designed to have 85% statistical power to show a difference between 
drug and placebo at conventional levels (ie, 5% level, 2-sided) of statistical significance.  
Based on the previous Pfizer pediatric study A1281132, the estimated difference in change 
from baseline of the YMRS total score for ziprasidone versus placebo is –4.55 points (from 
descriptive and LSMEANs at week 4) with an approximate within-group standard deviation 
of 8.0. 
The effect size used in the design of this study is 0.57, and is consistent with the weighted 
estimate of the effect size (0.65) of second generation antipsychotics in pediatric bipolar 
patients published in the recent meta-analysis of Correll et al, which was based on the results 
of multiple placebo-controlled trials.
Using EAST (version 5.4) for a two-sample t-test, the sample size needed to detect this 
difference with 85% power at a two-sided significance level of 5% was determined to be 
111 randomized subjects.  Assuming a 38% dropout rate, the original sample size for this 
study was 180 subjects.
The randomization will be stratified by weight group (weight <45 kg, weight ≥45 kg) to 
ensure treatment balance within each of the two weight groups. 
2.2.1. Re-estimation of Sample Size
During the conduct of the study, enrollment and subject disposition was monitored on a 
regular basis as part of the blinded data reviews prepared for presentation to the external Data 
Monitoring Committee. These reviews have revealed that the actual observed dropout rate in 
the study is substantially less than the 38% drop-out rate that was assumed for the original 
sample size estimation procedure. 
Based on these observations, the required sample size will be re-estimated by updating the 
original sample size dropout rate assumption to reflect the actual observed dropout rate, 
while maintaining all other power assumptions the same. 
The re-estimation will require the study to continue to have a minimum of 85% statistical 
power to show a difference between drug and placebo at conventional levels (ie, 5% level, 
2-sided) of statistical significance. The estimated difference in change from baseline of the 
YMRS total score for ziprasidone versus placebo is –4.55 points with an approximate 
within-group standard deviation of 8.0. The sample size needed to detect this difference with 
85% power at a two-sided significance level of 5% is 111 randomized subjects. Adjusting 
for dropouts (approximately 20% at week 4, based on the actual observed study drop-out 
rate), the total sample necessary is approximately 138 subjects (1:1 enrollment with 69 on 
ziprasidone and 69 on placebo).
Shortly after enrollment into this study commenced, Pfizer was informed by the rater training 
vendor (on 29 September 2014) that an internal audit had revealed an error in their internal 
processes.  This error resulted in some sites being notified that they could start screening 
subjects before all raters at the sites had completed all of the required rater training 
activities. The primary endpoint assessments (YMRS) and/or the diagnostic interviews 
(KSADS) of 14 subjects were impacted by the rater training issue.


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In agreement with the FDA to ensure the robustness of the inferential analysis, study 
committed to recruit an additional 14 subjects into the study and conduct a sensitivity 
analysis excluding these 14 subjects to mitigate the effect of the rater training issue that was 
identified (see Section 8.2.2).
During the study subject evaluability meeting, four additional subjects were identified as also 
having been impacted by a rater training issue affecting either the primary endpoint (YMRS) 
or the diagnostic interview (KSADS). 
With the additional 18 subjects enrolled to mitigate the impact of the rater training issue, and 
the modified assumption on the dropout rate, the total planned sample for this study is 
156 subjects (1:1 enrollment with 78 on ziprasidone and 78 on placebo). (See Table 1).
Table 1.
Sample Size Summary
Attribute
Original
Re-Estimation
Power
85%
85%
Difference
-4.55
-4.55
Standard Deviation
8.0
8.0
Alpha
0.05
0.05
Sides
2-sided
2-sided
N Required
111
111
Dropout Rate
38%
20%
Total N
180
138
Adjustment for Rater Training Situation
Number
14
18
Total w/Rater Adj.
194
156
2.3. Study Objectives
2.3.1. Primary Objectives
1. To assess the efficacy of oral ziprasidone compared with placebo in the treatment of 
children and adolescents aged 10- 17 with Bipolar I Disorder (current or most recent 
episode manic) as measured by the change from baseline to Week 4 in the Young 
Mania Rating Scale (YMRS) total score.
2. To evaluate the safety and tolerability of oral ziprasidone over 4 weeks in the 
treatment of children and adolescents with Bipolar I Disorder (current or most recent 
episode manic).
2.3.2. Secondary Objectives
The key secondary objective of the study is to evaluate the efficacy of oral ziprasidone as 
compared with placebo in the treatment of children and adolescents with Bipolar I Disorder 
(current or most recent episode manic) as measured by the change from baseline in the 
Clinical Global Impression of Severity (CGI-S) score.




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5. ANALYSIS SETS
The following sets are defined for use in the analyses: 
•
Intent-To-Treat (ITT) Analysis Set.
•
Per-Protocol (PP) Analysis Set.
•
Safety Analysis Set.
Both the ITT and PP analysis sets will be used in the analyses of all efficacy endpoints, with 
the ITT being primary. The Safety Analysis Set will be used in the analyses of the safety 
data. Only the ITT analysis set will be used in the analyses of the 
 outcome measure 
and special safety assessments (CSSRS data, CDRS, and movement disorder scales).
5.1. ITT Analysis Set
For this protocol, an intent-to-treat (ITT) analysis set will be defined as the set of all patients 
who were randomized, had baseline measurements, took at least 1 dose of study medication 
(Ziprasidone or placebo), and with at least 1 post-baseline visit. This definition of ITT may 
be considered a modified ITT definition; however, it will be referred to as ITT throughout the 
protocol and the SAP.
5.2. ‘Per Protocol’ Analysis Set 
The per-protocol (PP) analysis set will include all patients in the ITT set without major 
protocol violations considered to impact the interpretation of the primary efficacy endpoint. 
Protocol deviations will be reviewed to generate the list of subjects with significant 
deviations to be excluded from the PP analysis set. The PP exclusion criteria will be 
finalized prior to breaking the blind.
5.3. Safety Analysis Set
The safety analysis set will include all patients who were randomized and took at least 1 dose 
of study medication (ziprasidone or placebo).
5.4. Treatment Misallocations 
If a subject was:
•
Randomized but not treated, these subjects are by definition excluded from the 
efficacy and safety analyses as all analysis sets require subjects to receive at least 
1 dose of study medication.
•
Treated but not randomized, these subjects are by definition excluded from the 
efficacy and safety analyses since randomized treatment is missing.
•
Randomized but took incorrect treatment, then they will be reported under their 
randomized treatment group for all efficacy analyses but will reported under the 
treatment they received for all safety analyses.
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5.5. Protocol Deviations
The following describes any protocol deviations that relate to the PP analysis set stated in
Section 5.2:
5.5.1. Deviations Assessed Prior to Randomization
A protocol deviator is a subject who was wrongly enrolled into the study, when inclusion or 
exclusion criteria were not appropriately satisfied. See protocol sections 4.1 and 4.2.
5.5.2. Deviations Assessed Post-Randomization
Protocol deviations include but are not limited to the following: 
-
Violations on concomitant medications (See protocol section 5.5);
-
Lack of compliance (level to be defined case by case);
-
Dosing errors (eg, treatment misallocation, overdose/under-dose).
A full list of protocol deviations will be compiled for the study report prior to database 
closure.  All deviations will be reviewed, and a determination made for the handling of each 
case. This review will be documented in a note to the study file prior to un-blinding the 
study database.
6. ENDPOINTS AND COVARIATES
For summaries and analyses of change from baseline, baseline is defined as the pre-dose 
measurements for variables that have assessment at the Baseline Visit (Day 1), and it is 
defined as the most recent assessment prior to randomization for variables that have no 
assessment at the Baseline Visit. For the electrocardiogram (ECG) data, baseline will be 
defined as the mean of the pre-dose triplicates at the Baseline Visit. 
For collection schedules for all endpoints, please refer to the protocol.
6.1. Efficacy Endpoint(s)
6.1.1. Primary Efficacy Endpoint:

Change from baseline to Week 4 in Young Mania Rating Scale (YMRS) total score.
6.1.2. Key Secondary Efficacy Endpoint:

Change from baseline to Week 4 in Clinical Global Impression of Severity (CGI-S) 
score.
6.1.3. Secondary Endpoints:

Change from baseline to Weeks 1, 2 and 3 in the YMRS total score;

Change from baseline to Weeks 1, 2 and 3 in the CGI-S score;


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•
CGI-I scores at Weeks 1, 2, 3, and 4.
6.2. Safety Endpoints
6.2.1. Safety Assessments
•
Adverse event monitoring;
•
Concomitant treatment monitoring;
•
Clinical laboratory monitoring;
•
Physical Examinations;
•
Blood Pressure and Pulse;
•
Height, weight, BMI, BMI z-score, and waist circumference;
•
12-lead ECG.
6.2.2. Special Safety Assessments
•
Suicidality assessment monitoring via the Columbia-Suicide Severity Rating Scale 
(C-SSRS);
•
Child Depression Rating Scale - Revised (CDRS-R) monitoring;
•
Movement disorder scale (SARS, BAS, and AIMS) monitoring.
6.3. Covariates 
Baseline values and weight category will be included as a covariate in the statistical models 
used to analyze endpoints requiring analysis of covariance (ANCOVA) by the protocol. See
Section 8 for details.
7. HANDLING OF MISSING VALUES
For all analyses using mixed model repeated measures models no explicit imputation of 
missing values will be performed. No imputation techniques (for example: LOCF) will be 
used for analyzing the endpoint of this study.
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8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
8.1.1. Mixed Model Repeated Measures Analyses (MMRM)
The endpoints including the primary, key-secondary, and secondary endpoints will be 
analyzed using a mixed model repeated measures analysis of covariance (MMRM); 
treatment, visit, visit-by-treatment interaction, and weight category as fixed effects and 
baseline score (with the exception of CGI-I score) as a covariate. Subject effect will enter 
the MMRM model as a random effect. The estimation method used will be restricted 
maximum likelihood. An unstructured covariance matrix will be used in the REPEATED 
statement. In case SAS PROC MIXED fails to converge, other covariance matrix structures 
will be considered in the sequence of Toeplitz, First-Order Autoregressive, and Variance 
Components. The EMPIRICAL option will be specified to compute the estimated 
variance-covariance matrix of the fixed-effects parameters. Type III sums of squares will be 
used to test both main effects and interactions.
8.2. Statistical Analyses 
8.2.1. Primary Analysis
The primary efficacy endpoint is change from baseline in the YMRS score. The primary time 
point is Week 4. The primary endpoint will be analyzed using the MMRM model described 
in Section 8.1.1. The primary comparison will be between ziprasidone and placebo at 
Week 4, conducted as a two-sided test at 5% level of significance. Based on the specified 
model, the point estimate and 95% confidence interval (CI) for the difference in means 
between the two treatments will be constructed using the least squares means and 
appropriate standard errors.
If the test result is significant (p-value ≤0.05) and in favor of ziprasidone, then efficacy of 
flexibly-dosed oral ziprasidone in the treatment of children and adolescents with Bipolar I 
Disorder (current or most recent episode manic) will be established.
A sensitivity analysis will be done by adding an interaction term of treatment and weight 
category to the primary analysis model specified in Section 8.1.1.
Supplemental analyses of the primary variable will be performed to support the robustness of 
the conclusions drawn from the primary mixed models repeated measures analysis described 
above. These supplemental analyses will include the following:

Summaries of reasons for discontinuations by treatment group;

Pattern-mixture ANCOVA analysis of change from baseline YMRS scores.
For the pattern-mixture analysis, grouping of the subjects on the basis of their dropout or
missing-data patterns will be explored. ‘Patterns’ will be defined under the following two 
cases:


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Case 1:
Pattern 1A - all subjects who have completed the study
Pattern 1B - all subjects who have discontinued the study
Case 2:
Pattern 2A - all subjects who have YMRS score for Week 3 or beyond.
Pattern 2B - all subjects who do not have data beyond Week 2.
A mixed effects repeated measures analysis of covariance model will be used to analyze 
change from baseline in YMRS score under each of the above cases. These models will 
include terms for treatment, pattern (as defined above), weight category, treatment-by-pattern 
interaction, visit, treatment by visit interaction, and visit by pattern interaction as fixed 
effects, baseline as a covariate, and subject as random effect. The estimation method used 
will be restricted maximum likelihood. The covariance structure among repeated measures 
will be assumed to be adequately modeled using an unstructured matrix. In case SAS PROC 
MIXED fails to converge, other covariance matrix structures will be considered in the 
sequence of Toeplitz, First-Order Autoregressive, and Variance Components. The 
EMPIRICAL option (in SAS) will be specified to compute the estimated variance-covariance 
matrix of the fixed-effects parameters. Type III sums of squares will be used to test both 
main effects and interactions. The primary comparison will be between ziprasidone and 
placebo at Week 4, averaged over the missing data patterns, and conducted as a two-sided 
test at 5% level of significance. Based on the specified model, the point estimate and 95% 
confidence interval (CI) for the difference in means between the two treatments will be 
constructed using the least squares means and appropriate standard errors.
The percentage of subjects showing a 50% reduction in YMRS scores from baseline to 
Week 4 will be presented descriptively for each group. Additionally, descriptive statistics for 
change from baseline in YMRS score will be provided by treatment group and visit 
classification.
8.2.2. Sensitivity Analysis of the primary endpoint
The YMRS and/or KSADS data of 18 subjects were impacted by the rating training issue. A 
sensitivity analysis of the treatment effect on the primary endpoint, excluding these 
18 subjects from the analysis, will use the MMRM analysis specified in the Section 8.1.1.
This analysis will be conducted on the ITT population only.
8.2.3. Secondary Analyses
The secondary efficacy endpoints include:

Change from baseline to week 4 in the CGI-S score (key secondary endpoint);




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Data for height, weight, BMI, and waist circumference will be summarized by timepoint 
using descriptive statistics. Additionally, height, weight, and BMI will be standardized using 
CDC growth charts and the resulting z-scores presented in listings and frequency tables in 
1-unit intervals. In addition, frequency tables of above/below a 1-point increase in the 
z-scores for BMI will be presented.
All randomized subjects who receive at least one dose of study drug will be included in the 
safety analysis. All adverse events that are observed from the time of first dosing with study 
medication (at randomization) until the end of study participation will be included in the 
safety analysis. Adverse events that occurred during treatment with the antipsychotic 
medication will be reported separately if the event occurred prior to randomization.
All adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by treatment group. The incidence of 
treatment-emergent adverse events will be tabulated by treatment group and by system organ 
class. In addition, the incidence of serious adverse events and adverse events that cause 
withdrawal will be tabulated. All adverse events will be listed.
The following 3-tier approach will be used to summarize AEs.  Under this approach, AEs are 
classified into 1 of 3 tiers.  Different analyses will be performed for different tiers and will be 
documented in the statistical analysis plan as follows:
Tier-1 events: These are pre-specified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan.  This list may be updated, as more is understood 
about the drug. 
Tier-2 events: These are events that are not tier-1 but are “common”.  A MedDRA Preferred 
Term (PT) is defined as a tier-2 event if there are at least 4 in any treatment group.
Tier-3 events: These are events that are neither tier-1 nor tier-2 events.
The analysis of adverse events under the 3-tier approach is considered exploratory. There
will be no adjustment for multiple comparisons or stratification factors in the analyses. For
tier-1 and tier-2 events, the proportion of AEs observed in each treatment groups will be
presented along with the point estimates and associated 95% confidence intervals of the risk
difference for the ziprasidone group compared with placebo.
For tier-1 events p-values will be included in the presentations. AEs will be arranged in the
output sorted in descending point estimate of the risk difference within system organ class.
Footnotes in the outputs will include the methods used to derive any p-values and confidence
intervals as per Pfizer standards. The tier-1 AEs will be analyzed using the approach of Chan
and Zhang (1999)1 who inverted two one-sided tests at half the significance level each for
calculating P-values and confidence intervals. The list of tier-1 AEs is maintained in the 
Ziprasidone Safety Review Plan.
For tier-2 AEs, both proportion and 95% CIs will be generated using an asymptotic approach
(Proc Binomial). A MedDRA PT is defined as a tier-2 event if there are at least 4 in any
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(Crowe et al, 2009)3 suggests using the “Rule of 4” to define tier-2 events. The “Rule of 4”
says that if a trial has 400 or fewer patients per group and there are 4 or more subjects with a
given MedDRA PT in any treatment group, then that PT will be categorized as a tier-2 event.
For tier-3 events, simple proportions will be presented.
All clinical laboratory data will be subjected to clinical review, summarized by frequency of 
events and mean changes from baseline.
All vital sign measurements will be displayed in listings by subject for each sample collection 
date and time. The measurement taken immediately prior to randomization will be used as 
the baseline for calculating changes in vital signs.
Centrally over-read ECG variables will be summarized by mean change from baseline to 
each measurement time for heart rate, PR interval, QRS width, QT interval and QTcF 
(Fridericia correction) values. Baseline will be defined as the mean of the pre-dose 
triplicates at the Baseline Visit. Additionally, the incidence of categorical increases in QTc 
intervals will be provided. Categories for QTcF are 450 msec, 480 msec, and 500 msec. 
Categories for QTcF as change from baseline are 30 msec increase and 60 msec increase. 
QTcF is considered the primary QTc value for measurements of change and for clinical 
decision making as this correction is more accurate with changes in heart rate. To enable 
historical comparisons, categorical changes in QTcB (Bazett’s correction) also will be 
tabulated but clinical decisions and interpretation of data will be based on QTcF values.
The frequency of prior and concomitant medications will be summarized by treatment based 
on the WHO-drug coding dictionary.
8.2.6. Analyses of Special Safety Endpoints
The special safety assessments include:

CDRS-R;

C-SSRS;

Movement Disorder Scales (SARS, BAS, and AIMS).
For special safety assessments, descriptive statistics (n, mean, standard deviation, min, max, 
95% CI) by treatment group and visit for the change from baseline will be provided. 
For CDRS-R, a listing by treatment group and visit will be generated to include all the 
CRDS-R ratings for any subject who at any visit had a CDRS-R total score of 40 or more. 
These are subjects with the potential of developing depression.


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For all of the Movement Disorder Scales, descriptive statistics by treatment group and visit 
for change from baseline will be provided. For the SARS, the total score from the sum of all 
10 sub-items will be summarized. For the BAS, only the global clinical assessment item will 
be summarized. For the AIMS, only the sum of the first seven items (ie, movement cluster) 
will be summarized. In addition, the same change from baseline MMRM model used for the 
primary and secondary endpoints will be applied to the Movement Disorder Scales.
The prospectively collected C-SSRS item responses will be mapped to the C-CASA suicidality 
event codes. No formal statistical hypothesis testing will be undertaken. Listings of both the 
C-CASA categories as well as the underlying C-SSRS scale data will be prepared. In 
addition, a summary table of C-CASA category frequencies at screening, baseline, and all 
post-baseline visits without regard to baseline will be compiled. Additional tables displaying 
post-baseline worsening and new-onset of suicidality within reporting categories (suicidal 
ideation) will also be prepared.


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8.2.7. Summary of Efficacy Analyses
Table 2.
Summary of Efficacy Analyses
Endpoint
Analysis Set
Statistical 
Method
Objective
Change from baseline in YMRS total score at Week 4
ITT
MMRM
Primary Analysis
Change from baseline in YMRS total score at Week 4
PP
MMRM
Supportive of Primary Analysis
Change from baseline in YMRS total score at Week 4 
– Sensitivity analysis (without 18 subjects)
ITT
MMRM
Sensitivity analysis of primary 
endpoint
Change from baseline in YMRS total score at Week 4 
with interaction term of treatment and weight
ITT
MMRM
Sensitivity analysis of primary 
endpoint 
Change from baseline in YMRS total score at Week 4
– Pattern Mixture Analyses
ITT
MMRM
Supportive of Primary Analysis
Change from baseline in YMRS total score at Week 4
– Pattern Mixture Analyses
PP
MMRM
Supportive of Primary Analysis
Change from baseline to week 4 in the CGI-S score
ITT
MMRM
Key-Secondary Analysis
Change from baseline to week 4 in the CGI-S score
PP
MMRM
Supportive of Key-Secondary Analysis
Change from baseline in YMRS total score and CGI-S 
score at Weeks 1, 2 and 3
ITT
MMRM
Secondary Analysis
Change from baseline in YMRS total score and CGI-S 
score at Weeks 1, 2 and 3
PP
MMRM
Supportive of Secondary Analysis
CGI-I score at weeks 1, 2, 3 and 4
ITT
MMRM
Secondary Analysis
CGI-I score at weeks 1, 2, 3 and 4
PP
MMRM
Supportive of Secondary Analysis
Descriptive summaries are not included in this summary.
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9. REFERENCES 
1.
Chan ISF, Zhang Z. (1999). Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics, 55:1201–1209.
2.
Correll CU, Sheridan EM, et al. (2010). Antipsychotic and mood stabilizer efficacy and 
tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis 
of acute, randomized, placebo-controlled trials.  Bipolar Disorders, 12:116-141.
3.
Crowe B, Xia HA, Berlin JA, et al. (2009). Recommendations for safety planning, data
collection, evaluation and reporting during drug, biologic and vaccine development: a 
report of the safety planning, evaluation and reporting team. Clinical Trials, 6:430-440.
4.
Ameena Isa, MD, Ira Bernstein, PhD, Madhukar Trivedi, et al (2014) Childhood 
Depression Subscales Using Repeated Sessions on Children’s Depression Rating Scale 
– Revised (CDRS-R) Scores. Journal of Child and Adolescent Psychopharmacology 
Volume 24, Number 6, 2014 Pp. 318–324 DOI: 10.1089/cap.2013.0127
5.
Longitudinal Data Analysis by Donald Hedeker and Robert D Gibbons Copyright 
@2006 John Wiley & Sons. Inc 




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Appendix 1.3. Sample SAS Code for the CGI-I Raw Scores MMRM Analyses
Sample SAS code to fit the MMRM model specified in 8.1.1 is given below, except there is 
no baseline in model.  The response variable actual is the actual score at each study visit, 
Trtpn is the treatment group, avisitn is the assigned visit and blwcat is baseline weight 
category.
PROC MIXED DATA=xxxx EMPIRICAL; 
class trtpn avisitn blwcat usubjid;
model actual = trtpn avisitn wtcat trtpn*avisitn / ddfm=kr2;
repeated avisitn /subject= usubjid r type=UN rcorr covb;
lsmeans trtpn*avisitn trtpn/ pdiff CL; 
RUN;
ODS OUTPUT Diffs=diff 
            LSMEANS = lsmeans;
Run;
Appendix 1.4. Sample SAS Code for the Pattern Mixture Models Case 1 and Case 2
Description of variables:
The response variable chg is the change from baseline at the study visits, Trtpn is the 
treatment group, avisitn is the assigned visit and blwcat is baseline weight category.
Case 1: dropout variable defined as binary (0= All subjects who have YMRS score for 
Week 4, 1 = All subjects who do not have data at Week 4)
avgbase as average baseline value of all patients
pcomp1 as proportion completers in Ziprasidone (Number of completers in Zip/Total 
number of patients in Zip)
pdisc1 as proportion dropouts in Ziprasidone (Number of dropouts in Zip/Total number of 
patients in Zip)
pcomp2 as proportion completers in placebo
pdisc2 as proportion dropouts in placebo
pct_compldif as pcomp1 - pcomp2
pct_discdif as pdisc1 - pdisc2
Notes to the model below:
(1) The different estimates statements are used to illustrate how the construction of the last 
estimate statement ZIPRASIDONE vs PLACEBO Averaged over Patterns is done. Same for 
the difference of ZIPRASIDONE Averaged over Patterns and PLACEBO Averaged over 
Patterns.


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(2) Case 1: As the dropout subgroup has no records on the last visit week 4, there are no 
corresponding coefficients, and these are hence ignored in estimate specification (in 
particular three-way interaction coefficients).
PROC MIXED DATA=xxxx EMPIRICAL; 
class avisitn trtpn usubjid blwcat dropout;
model chg=blwcat base avisitn trtpn avisitn*trtpn 
      dropout dropout*avisitn dropout*trtpn avisitn*trtpn*dropout / solution covb;
repeated avisitn /subject= usubjid r type=UN;
estimate "ZIPRASIDONE in Completers"          
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 1 0 dropout 1 0  avisitn*trtpn 0 0 0 0 0 0 1 0
avisitn*dropout 0 0 0 0 0 0 1 0 trtpn*dropout 1 0 0 0 avisitn*trtpn*dropout 0 0 0 0 0 0 0 0 0 0
0 0 1 0 / cl singular=1;
   
estimate "ZIPRASIDONE in Discontinuations"    
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 1 0 dropout 0 1 avisitn*trtpn 0 0 0 0 0 0 1 0
trtpn*dropout 0 1 0 0/ cl singular=1;
   
estimate "ZIPRASIDONE Averaged over Patterns" 
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 1 0 dropout pcomp1 pdisc1 avisitn*trtpn 0 0 0
0 0 0 1 0 avisitn*dropout 0 0 0 0 0 0 pcomp1 0 trtpn*dropout pcomp1 pdisc1 0 0
avisitn*trtpn*dropout 0 0 0 0 0 0 0 0 0 0 0 0 pcomp1 0 0 0/ cl singular=1;
   
estimate "PLACEBO in Completers" 
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 0 1 dropout 1 0 avisitn*trtpn 0 0 0 0 0 0 0 1
avisitn*dropout 0 0 0 0 0 0 1 trtpn*dropout 0 0 1 0 avisitn*trtpn*dropout 0 0 0 0 0 0 0 0 0 0 0
0 0 1 0 0/ cl singular=1;
   
estimate "PLACEBO in Discontinuations"        
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 0 1 dropout 0 1 avisitn*trtpn 0 0 0 0 0 0 0 1
trtpn*dropout 0 0 0 1 / cl singular=1;
   
estimate "PLACEBO Averaged over Patterns"  
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 0 1 dropout pcomp2 pdisc2 avisitn*trtpn 0 0 0
0 0 0 0 1 avisitn*dropout 0 0 0 0 0 0 pcomp2 0 trtpn*dropout 0 0 pcomp2 pdisc2
avisitn*trtpn*dropout 0 0 0 0 0 0 0 0 0 0 0 0 0 pcomp2 0 0 / cl singular=1;
   
estimate "ZIPRASIDONE vs PLACEBO Averaged over Patterns"                                     
trtpn 1 -1 dropout pct_compldif pct_discdif avisitn*trtpn 0 0 0 0 0 0 1 -1 avisitn*dropout 0
0 0 0 0 0 pct compldif 0 trtpn*dropout pcomp1 pdisc1 -pcomp2 -pdisc2
avisitn*trtpn*dropout 0 0 0 0 0 0 0 0 0 0 0 0 pcomp1 -pcomp2 0 0 / cl singular=1;
ods output estimates=estimates1;


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Case 2: dropout variable defined as binary (0= All subjects who have YMRS score for 
Week 3 or beyond, 1 = All subjects who do not have data beyond Week 2)
avgbase as average baseline value of all patients
pcomp1 as proportion completers in Ziprasidone (Number of completers in Zip/Total 
number of patients in Zip)
pdisc1 as proportion dropouts in Ziprasidone (Number of dropouts in Zip/Total number of 
patients in Zip)
pcomp2 as proportion completers in placebo
pdisc2 as proportion dropouts in placebo
pct_compldif as pcomp1 - pcomp2
pct_discdif as pdisc1 - pdisc2
Notes to the model below:
(1) The different estimates statements are used to illustrate how the construction of the last 
estimate statement ZIPRASIDONE vs PLACEBO Averaged over Patterns is done. Same for 
the difference of ZIPRASIDONE Averaged over Patterns and PLACEBO Averaged over 
Patterns.
Case 2: This code is very similar to case 1, except that the proportion of dropouts and 
completers will be different, also there will not be records for the last 2 visits in the dropout 
group, the week 3 related coefficients for dropouts will also not be available.
PROC MIXED DATA=xxxx EMPIRICAL; 
class avisitn trtpn usubjid blwcat dropout;
model chg=blwcat base avisitn trtpn avisitn*trtpn 
      dropout dropout*avisitn dropout*trtpn avisitn*trtpn*dropout / solution covb;
repeated avisitn /subject= usubjid r type=UN;
estimate "ZIPRASIDONE in Completers"         
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 1 0 dropout 1 0 avisitn*trtpn 0 0 0 0 0 0 1 0
avisitn*dropout 0 0 0 0 0 1 trtpn*dropout 1 0 0 0 avisitn*trtpn*dropout 0 0 0 0 0 0 0 0 0 0 1 0
/ cl singular=1;
  
estimate "ZIPRASIDONE in Discontinuations"   
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 1 0 dropout 0 1 avisitn*trtpn 0 0 0 0 0 0 1 0
trtpn*dropout 0 1 0 0/ cl singular=1;
  
estimate "ZIPRASIDONE Averaged over Patterns" 
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 1 0 dropout pcomp1 pdisc1 avisitn*trtpn 0 0 0
0 0 0 1 0 avisitn*dropout 0 0 0 0 0 pcomp1 trtpn*dropout pcomp1 pdisc1 0 0
avisitn*trtpn*dropout 0 0 0 0 0 0 0 0 0 0 pcomp1 0/ cl singular=1;
estimate "PLACEBO in Completers" 


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intercept 1 base avgbase avisitn 0 0 0 1 trtpn 0 1 dropout 1 0 avisitn*trtpn 0 0 0 0 0 0 0 1
avisitn*dropout 0 0 0 0 0 1 trtpn*dropout 0 0 1 0 avisitn*trtpn*dropout 0 0 0 0 0 0 0 0 0 0 0
1/ cl singular=1;
  
estimate "PLACEBO in Discontinuations"       
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 0 1 dropout 0 1 avisitn*trtpn 0 0 0 0 0 0 0 1
trtpn*dropout 0 0 0 1 / cl singular=1;
  
estimate "PLACEBO Averaged over Patterns" 
intercept 1 base avgbase avisitn 0 0 0 1 trtpn 0 1 dropout pcomp2 pdisc2 avisitn*trtpn 0 0 0
0 0 0 0 1 avisitn*dropout 0 0 0 0 0 pcomp2 trtpn*dropout 0 0 pcomp2 pdisc2
avisitn*trtpn*dropout 0 0 0 0 0 0 0 0 0 0 0 pcomp2 / cl singular=1;
  
estimate "ZIPRASIDONE vs PLACEBO Averaged over Patterns"                                    
trtpn 1 -1 dropout pct_compldif pct_discdif avisitn*trtpn 0 0 0 0 0 0 1 -1 avisitn*dropout 0
0 0 0 0 pct compldif trtpn*dropout pcomp1 pdisc1 -pcomp2 -pdisc2 avisitn*trtpn*dropout 
0 0 0 0  0 0 0 0  0 0 pcomp1 -pcomp2 / cl singular=1;
ods output estimates=estimates2;


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Appendix 2. VISIT WINDOW 
For by-visit inferential analyses on YMRS total score, CGI-S, and CGI-I, if a subject 
discontinued early from the study, the corresponding ET Visit will be re-slotted back to 
earlier nominal visits according to the duration since first dosing date. Assuming FACTDAT 
is the first study medication date and COLLDATE is the date of visit to be re-slotted, 
windowing will follow the below algorithm:
IF -99 <= COLLDATE - FACTDAT + 1 <= 0 THEN VISIT = SCREENING;
IF COLLDATE - FACTDAT + 1 = 1 THEN VISIT = BASELINE;
IF 2 <= COLLDATE - FACTDAT + 1 <= 10 THEN VISIT = WEEK 1;
IF 11 <= COLLDATE - FACTDAT + 1 <= 17 THEN VISIT = WEEK 2;
IF 18 <= COLLDATE - FACTDAT + 1 <= 24 THEN VISIT = WEEK 3;
IF 25 <= COLLDATE - FACTDAT + 1 <= 31 THEN VISIT = WEEK 4;
IF COLLDATE - FACTDAT + 1> 31 THEN VISIT= FU WEEK 5;