Clinical trial NCT03768726
Conditions: Bipolar Disorder
Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Start date: 2018-12-21; Completion date: 2020-07-31
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This 26-week open-label extension study is designed to provide information on the safety and tolerability of oral ziprasidone (20-80 mg BID (twice daily) with meals) during long-term administration in children and adolescents with Bipolar I Disorder (current or most recent episode manic).

Detailed description:
Study A1281201 is a 6 month, open label extension study of the ongoing double blind, randomized, placebo controlled study of ziprasidone in pediatric Bipolar Disorder (Study A1281198). Study A1281201 will enroll adolescents aged 10 to 17 years with Bipolar I Disorder who have participated in double blind Study A1281198. In order to be enrolled in this open label extension trial, subjects must have met the enrollment criteria for Study A1281198, and must meet the inclusion and exclusion criteria for Study A1281201 at the extension study Baseline visit (last visit in the double blind study).

The purpose of adding this extension study to the ongoing Geodon pediatric bipolar program is to obtain additional longer term safety data in children and adolescents with Bipolar I disorder treated with ziprasidone.

Arms: arm 1: All investigational products will be provided by Pfizer and will include oral ziprasidone capsules of 20, 40, 60, and 80 mg strength. Matching placebo capsules will also be supplied for the initial 1-14 day dose transition period. During the transition period all subjects will receive both active ziprasidone and placebo capsules. The placebo capsules are used to maintain the blind to the treatment assignment of the subjects in A1281198 . All medication will be packaged in childproof blister cards with columns for AM and for PM capsules. During the dose transition period (Weeks 1-2, Days 1-14), subjects will receive a study drug blister card for each week of transition dosing. Subjects weighing greater than 45 kg will receive 2 weeks of transition medication, while subjects weighing less than 45 kg will receive 1 week of transition medication.
Interventions: intervention 1: Ziprasidone intervention 2: Placebo
Intervention descriptions: intervention 1: All investigational products will be provided by Pfizer and will include oral ziprasidone capsules of 20, 40, 60, and 80 mg strength. Matching placebo capsules will also be supplied for the initial 1-14 day dose transition period. During the transition period all subjects will receive both active ziprasidone and placebo capsules. The placebo capsules are used to maintain the blind to the treatment assignment of the subjects in A1281198 . All medication will be packaged in childproof blister cards with columns for AM and for PM capsules. During the dose transition period (Weeks 1-2, Days 1-14), subjects will receive a study drug blister card for each week of transition dosing. Subjects weighing greater than 45 kg will receive 2 weeks of transition medication, while subjects weighing less than 45 kg will receive 1 week of transition medication. intervention 2: All investigational products will be provided by Pfizer and will include oral ziprasidone capsules of 20, 40, 60, and 80 mg strength. Matching placebo capsules will also be supplied for the initial 1-14 day dose transition period. During the transition period all subjects will receive both active ziprasidone and placebo capsules. The placebo capsules are used to maintain the blind to the treatment assignment of the subjects in A1281198 . All medication will be packaged in childproof blister cards with columns for AM and for PM capsules. During the dose transition period (Weeks 1-2, Days 1-14), subjects will receive a study drug blister card for each week of transition dosing. Subjects weighing greater than 45 kg will receive 2 weeks of transition medication, while subjects weighing less than 45 kg will receive 1 week of transition medication.

Protocol documents:
Prot_000.pdf: 
CP-88,059-1
A1281201
Final Protocol Amendment 1, 19 February 2019 
PFIZER CONFIDENTIAL
Page 1
26-WEEK OPEN-LABEL EXTENSION STUDY EVALUATING THE SAFETY AND 
TOLERABILITY OF FLEXIBLE DOSES OF ORAL ZIPRASIDONE IN CHILDREN 
AND ADOLESCENTS WITH BIPOLAR I DISORDER (MOST RECENT EPISODE 
MANIC)
Investigational Product Number:
CP-88,059-1
Investigational Product Name:
Ziprasidone Hydrochloride 
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable
Protocol Number:
A1281201
Phase:
3
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, 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.
CCI


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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
13 August 2018
Amendment 1
16 February 2019
Amendment 1 19 February 2019
For this amendment there no substantial 
changes to the study only non-substantial 
changes noted below: 
Corrections have been applied to the text to 
be consistent with schedule of activities.  
Clarification on enrollment eligibility, 
baseline data and transition period 
provided for subjects from parent study 
(A1281198).
In addition, formatting, clerical and 
grammar updates have been addressed 
within this amendment.
Non-Substantial:
PROTOCOL SUMMARY, Trial Design
PROTOCOL SUMMARY, Trial 
Treatments
PROTOCOL SUMMARY, Statistical 
Methods
SCHEDULE OF ACTIVITIES
3. STUDY DESIGN
4.1. Inclusion Criteria
5.4.2. Preparation and Dispensing
5.5. Administration, Open-Label Weeks 3-
26
5.9 Concomitant Treatment
6.1. Baseline Visit
6.2. Study Visits During Open-label 


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Treatment
6.3 Follow up Visit
7.1.2 Clinical Laboratory Testing
7.1.4. Blood Pressure and Pulse
7.2 Electrocardiograms
7.3.1. Child Depression Rating Scale –
Revised (CDRS-R)
7.3.2.4. Columbia Suicide Severity Rating 
Scale (C-SSRS)
7.4.1. Young Mania Rating Scale (YMRS)
7.4.3. Children’s Global Assessment Scale
9.1. Sample Size Determination
9.2. Efficacy Analysis
Appendix 2. Criteria for Training Approval 
without Sponsor
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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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
APPENDICES ...........................................................................................................................8
PROTOCOL SUMMARY.........................................................................................................9
SCHEDULE OF ACTIVITIES................................................................................................13
1. INTRODUCTION ...............................................................................................................15
1.1. Mechanism of Action/Indication.............................................................................15
1.2. Background and Rationale ......................................................................................15
1.2.1. Background on Ziprasidone (CP-88,059-1) ...............................................16
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................17
3. STUDY DESIGN.................................................................................................................17
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................18
4.1. Inclusion Criteria.....................................................................................................19
4.2. Exclusion Criteria....................................................................................................20
4.3. Randomization Criteria ...........................................................................................21
4.4. Lifestyle Requirements ...........................................................................................21
4.4.1. Contraception..............................................................................................21
4.5. Sponsor’s Qualified Medical Personnel..................................................................22
5. STUDY TREATMENTS.....................................................................................................22
5.1. Allocation to Treatment ..........................................................................................22
5.2. Breaking the Blind ..................................................................................................23
5.3. Subject Compliance.................................................................................................23
5.4. Investigational Product Supplies.............................................................................24
5.4.1. Dosage Form and Packaging ......................................................................24
5.4.2. Preparation and Dispensing........................................................................25
5.5. Administration.........................................................................................................31
5.6. Summary of the Dose Titration Schedule for Study A1281201 .............................32
5.7. Investigational Product Storage ..............................................................................33
5.8. Investigational Product Accountability...................................................................34
5.8.1. Destruction of Investigational Product Supplies ........................................34
5.9. Concomitant Treatment(s).......................................................................................34
6. STUDY PROCEDURES .....................................................................................................36


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6.1. Baseline Visit ..........................................................................................................36
6.2. Study Visits During Open-label Treatment.............................................................37
6.3. Follow-up Visit .......................................................................................................39
6.4. Subject Withdrawal.................................................................................................39
7. ASSESSMENTS..................................................................................................................43
7.1. Safety Assessments .................................................................................................43
7.1.1. Adverse Events...........................................................................................43
7.1.2. Clinical Laboratory Testing........................................................................43
7.1.3. Physical Examinations................................................................................44
7.1.4. Blood Pressure and Pulse............................................................................44
7.1.5. Body Weight and Height, BMI, Waist Circumference...............................45
7.2. Electrocardiograms..................................................................................................45
7.3. Special Safety Assessments ....................................................................................46
7.3.1. Child Depression Rating Scale – Revised (CDRS-R)................................46
7.3.2. Movement Disorder Scales.........................................................................46
7.3.2.1. Simpson-Angus Rating Scale (SARS)......................................46
7.3.2.2. Barnes Akathisia Rating Scale (BAS).......................................47
7.3.2.3. Abnormal Involuntary Movement Scale (AIMS) .....................47
7.3.2.4. Columbia Suicide Severity Rating Scale (C-SSRS) .................47
7.4. Efficacy Assessments..............................................................................................48
7.4.1. Young Mania Rating Scale (YMRS)..........................................................48
7.4.2. Clinical Global Impression of Severity Scale (CGI-S)...............................49
7.4.3. Children’s Global Assessment Scale..........................................................49
7.5. Pregnancy Testing...................................................................................................49
7.6. Rater Qualifications/Training/Certification for Diagnostic, Efficacy, and 
Safety Rating Scales..................................................................................................50
8. ADVERSE EVENT REPORTING......................................................................................50
8.1. Requirements...........................................................................................................50
8.1.1. Additional Details on Recording Adverse Events on the CRF...................51
8.1.2. Eliciting Adverse Event Information..........................................................52
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................52
8.1.4. Time Period for Collecting AE/SAE Information......................................52


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8.1.4.1. Reporting SAEs to Pfizer Safety...............................................52
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................52
8.1.5. Causality Assessment .................................................................................53
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................53
8.2. Definitions...............................................................................................................53
8.2.1. Adverse Events...........................................................................................53
8.2.2. Abnormal Test Findings .............................................................................54
8.2.3. Serious Adverse Events ..............................................................................54
8.2.4. Hospitalization............................................................................................55
8.3. Severity Assessment................................................................................................56
8.4. Special Situations ....................................................................................................56
8.4.1. Protocol-Specified Serious Adverse Events...............................................56
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................57
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................58
8.4.3.1. Exposure During Pregnancy......................................................59
8.4.3.2. Exposure During Breastfeeding ................................................60
8.4.3.3. Occupational Exposure .............................................................60
8.4.4. Medication Errors and Lack of Efficacy ....................................................60
8.4.4.1. Medication Errors......................................................................61
8.4.4.2. Lack of Efficacy........................................................................61
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................61
9.1. Sample Size Determination.....................................................................................62
9.2. Efficacy Analysis ....................................................................................................62
9.3. Safety Analysis........................................................................................................62
9.4. Interim Analysis ......................................................................................................63
9.5. Data Monitoring Committee ...................................................................................63
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................64
11. DATA HANDLING AND RECORD KEEPING .............................................................64
11.1. Case Report Forms/Electronic Data Record .........................................................64
11.2. Record Retention...................................................................................................65
12. ETHICS..............................................................................................................................66


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12.1. Institutional Review Board/Ethics Committee......................................................66
12.2. Ethical Conduct of the Study ................................................................................66
12.3. Subject Information and Consent..........................................................................66
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................67
13. DEFINITION OF END OF TRIAL...................................................................................68
13.1. End of Trial in a Member State.............................................................................68
13.2. End of Trial in All Other Participating Countries.................................................68
14. SPONSOR DISCONTINUATION CRITERIA ................................................................68
15. PUBLICATION OF STUDY RESULTS..........................................................................68
15.1. Communication of Results by Pfizer ....................................................................68
15.2. Publications by Investigators ................................................................................69
16. REFERENCES ..................................................................................................................71
LIST OF TABLES
Table 1.
Double-Blind Dose Transition Blister Cards for 45 kg Subjects on 
160 mg/day or 140 mg/day of Active Ziprasidone or Placebo at End of 
Study A1281198, Weeks 1 and 2 .........................................................................26
Table 2.
Double-Blind Dose Transition Blister Cards for 45 kg Subjects on 
120 mg/day of Active Ziprasidone or Placebo at End of Study A1281198, 
Weeks 1 and 2.......................................................................................................26
Table 3.
Double-Blind Dose Transition Blister Cards for 45 kg Subjects on 
80 mg/day or 100 mg of Active Ziprasidone or Placebo at End of 
Study A1281198, Weeks 1 and 2 .........................................................................27
Table 4.
Double Blind Dose Transition Blister Cards for <45 kg Subjects on 
40 mg/day, 60 mg/day, or 80 mg of Active Ziprasidone or Placebo at End 
of Study A1281198, Week 1 ................................................................................28
Table 5.
40 mg Fixed Dose Regimen .................................................................................28
Table 6.
60 mg Fixed Dose Regimen .................................................................................29
Table 7.
80 mg Fixed Dose Regimen .................................................................................29
Table 8.
100 mg Fixed Dose Regimen ...............................................................................29
Table 9.
120 mg Fixed Dose Regimen ...............................................................................30
Table 10.
140 mg Fixed Dose Regimen ...............................................................................30
Table 11.
160 mg Fixed Dose Regimen ...............................................................................30
Table 12.
Prohibited/Concomitant Medication Table...........................................................35


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APPENDICES
Appendix 1. Abbreviations......................................................................................................73
Appendix 2. Criteria for Training Approval without Sponsor Review ...................................76


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PROTOCOL SUMMARY
Indication:
Study A1281201 is a 6-month, open label extension study of the ongoing double-blind, 
randomized, placebo controlled study of ziprasidone in pediatric Bipolar Disorder 
(Study A1281198).  Study A1281201 will enroll adolescents aged 10 to 17 years with
Bipolar I Disorder who have participated in double blind Study A1281198. In order to be 
enrolled in this open label extension trial, subjects must have met the enrollment criteria for 
Study A1281198, and must meet the inclusion and exclusion criteria for Study A1281201 at 
the extension study Baseline visit (last visit in the double blind study).
Rationale:
The purpose of adding this extension study to the ongoing Geodon pediatric bipolar program 
is to obtain additional longer term safety data in children and adolescents with Bipolar I 
disorder treated with ziprasidone.
Trial Design:
This 26-week open-label extension study is designed to provide information on the safety 
and tolerability of oral ziprasidone (20-80 mg BID (twice daily) with meals) during 
long-term administration in children and adolescents with Bipolar I Disorder (current or most 
recent episode manic).  It will enroll subjects who have participated in the 4-week, 
double-blind, placebo-controlled safety and efficacy trial, Study A1281198, meet study entry 
criteria, and wish to receive treatment with open-label ziprasidone.
The final visit of the double-blind trial (Week 4 or early termination) will serve as the 
Baseline Visit for the extension study.  During the first 1-14 days of the study, subjects will 
be transitioned under double-blind conditions to treatment with open label ziprasidone.  The 
dosing of ziprasidone will be flexible in Weeks 3-26 of this study.
Post-Baseline visits will occur at Weeks 1, 2, 4, 6, 10, 14, 18, 22, 26 during treatment, with a 
follow-up visit at Week 27.
A telephone call must occur 28 to 35 days from administration of the final dose of 
investigational product to capture any potential adverse events and to confirm appropriate 
contraception usage.
Endpoints:
Safety Assessments:

Adverse event reporting;

Clinical laboratory testing;

Physical examinations;


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
Blood pressure and pulse;

Height and weight;

Body Mass Index (BMI), BMI Z-score;

Waist circumference;

Electrocardiograms, including QT interval corrected for rate (QTc).
Special Safety Assessments:

Movement Disorder Scales - Simpson Angus Rating Scale (SARS), Barnes Akathisia 
Rating Scale (BAS), and Abnormal Involuntary Movement Scale(AIMS);

Columbia Suicide Severity Rating Scale (C-SSRS);

Child Depression Rating Scale (CDRS- R).
Efficacy Assessments:

Young Mania Rating Scale; 

Clinical Global Impression of Severity (CGI-S);

Children’s Global Assessment Scale (CGAS).
Trial Treatments:
All investigational products will be provided by Pfizer and will include oral ziprasidone 
capsules of 20, 40, 60, and 80 mg strength.  Matching placebo capsules will also be supplied 
for the initial 1-14 day dose transition period.  All medication will be packaged in childproof 
blister cards with columns for AM and for PM capsules.
During the dose transition period (Weeks 1-2, Days 1-14), subjects will receive a study drug 
blister card for each week of transition dosing. Subjects weighing 45 kg will receive 
2 weeks of transition medication, while subjects weighing less than <45 kg will receive 
1 week of transition medication.
At the baseline visit of the A1281201 study, subjects will transition onto active medication if 
previously assigned to the placebo group or continue on active study drug.  Over the course 
of the double-blind dose transition period, subjects <45 kg will be transitioned to a total daily 
dose of 60 mg a day by Day 7 of Week 1 and subjects 45 kg will be transitioned to a total 
daily dose of 120 mg a day by Day 10 of Week 2.  (Subjects on 160 mg, 140 mg, 100 mg, 
and 80 mg active at the end of Study A1281198 will all be transitioned to 120 mg a day at the 
end of the two-week transition period. Subjects on 120 mg active at the end of 
Study A1281198 will remain on 120 mg a day through the dose transition period).


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During the dose transition period, investigators, subjects, and the study team will be kept 
blinded to the content of the dose transition cards (which contain both placebo and active 
ziprasidone capsules) but not to the dose level of study medication.
Dose level for each day of the transition dosing card for subjects who were on placebo or 
ziprasidone in Study A1281198 are provided in Table 1, Table 2, Table 3 and Table 4.
Any subject who cannot tolerate the transition study medication during Week 1 should 
be discontinued from the study.
After the Week 2 visit for the >45 kg subjects and after the Week 1 visit for the <45 kg 
subjects, dosing will be open label and flexible, with dosing adjustments made at the 
discretion of the investigator to maintain optimal efficacy and tolerability. The target dose 
range for subjects <45 kg is 60 mg to 80 mg/day and for subjects >45 kg, 120 mg to 160 
mg/day, which are identical to the target dose ranges used in Study A1281198.
The blister cards for Weeks 3-26 will each contain medication for 8 days. Two blister cards 
will be dispensed at Weeks 2 and 4 and then 4 blister cards will be dispensed at each monthly 
visit from the Weeks 6 visit through the Week 22 visit.  Dose increases should be limited to 
20 mg a week during Weeks 6-22 of the flexible dosing weeks of the study. However, 
subjects 45 weight can be increased to 160 mg a day after they have been on a stable dose 
of 120 mg a day if clinically indicated. Table 1, Table 2, Table 3 and Table 4 provide the 
dose transition schedule for all possible dose levels for subjects in both weight categories.
Statistical Methods:
Sample Size
The number of subjects entering this open-label trial will be determined by the number of 
subjects electing to continue treatment after completing or withdrawing from the preceding 
double blind study, A1281198.  We estimate that approximately 55 subjects randomized in 
the double blind study (based on the increased sample size of N (number) =194 subjects) will 
be eligible to continue in this open label extension.  With an expected dropout rate of 
approximately 35%, this gives an estimate of approximately 40 subjects to complete this 
26 week open label study (if all 55 subjects enter the extension study).
Data Summarization Methods
As this is an open label study with no comparator, no inferential statistics will be performed. 
Quantitative variables will be described by standard descriptive statistics (n, mean, standard 
deviation, minimum, and maximum, 95% confidence intervals), and qualitative variables will 
be summarized by frequency tables.  Summaries will include data for all subjects who took at 
least one dose of investigational product in this open label extension study.
Baseline values for efficacy, outcomes and special safety endpoints will be the last 
observation made prior to the subject’s receiving open label treatment.  For safety, for those 
subjects who were randomized to placebo in the double blind study, baseline values will be 


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the last observation prior to initiating dosing in the open label extension study (normally, the 
observation of the last visit in the double blind study); and for those subjects who were 
randomized to ziprasidone in the double blind study, baseline values will the last observation 
prior to initiating dosing in the double blind study (normally, the value from the Baseline 
visit in the double blind study).
Safety data from this trial will be monitored by the independent Data Monitoring Committee 
(DMC) currently monitoring study A1281198.  Details of the board’s functions are
documented in the DMC Charter.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
Refer to the STUDY PROCEDURES and ASSESSMENTS sections of the protocol for 
detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities table, in order to conduct evaluations or assessments required to protect 
the well-being of the subject.
Activities/
Assessments
Baselinea
Open-label Ziprasidone
Follow
up Visit
Follow 
Up l
Visit Windowsb
      1 Day
3 days
Visit
1
2
3
4
5
6
7
8
9
10
11
12
Visit Schedule     
Day 1
W1
W2
W4
W6
W10
W14
W18
W22
W26/
ETa
W27
Informed Consent, Assentc
X
Inclusion/Exclusion
X
Physical Exam
X
X
Body Weight/Height/
BMI/BMI-z score/ waist 
circumference
X
X
X
Xd
ECG*,e
X
X
X
X
X
X
X
X
Xd
Blood Pressure/Pulsef f
X
X
X
X
X
X
X
X
X
X
Xd
Chem/Hemato/Urinalysis
X
X
X
Xd
Hormones (free T4 & TSH, 
Prolactin) 
X
X
X
Xd
Fasting glucose, lipids, 
insulin, HbA1c**
X
X
X
X
Xd
Urine drug screeng
X
X
X
Urine Pregnancy Testh
X
X
X
X
X
X
X
X
X
X
X
Verification of 
contraception 
X
X
X
X
X
X
X
X
X
X
X
Xl
Dispense Double-Blind 
Transition Cardj,m
X
Xm,j
Dispense Study Drug
X
X
X
X
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
X
X
X
Subject telephone contacti
X
X
X
X
X
X
X
Xl
YMRS
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
X
CGAS
X
X
CDRS-R
X
X
X
X
X
X
X
X
X
X
Xd
SARS, BAS, AIMS
X
X
X
X
X
X
X
X
X
X
Xd
C-SSRSk
X
X
X
X
X
X
X
X
X
X
X
Serious and non-serious 
adverse event monitoring
X
X
X
X
X
X
X
X
X
X
X
Xl
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
ET = early termination; BMI = Body Mass Index; ECG = Electrocardiogram; T4 = Thyroxin 4; TSH= Thyroid-Stimulating 
Hormone; HbA1c = glycated hemoglobin; YMRS = Young Mania Rating Scale; CGI-S = Clinical Global Impressions of
Severity; CGAS =Children’s Global Assessment Scale; CDRS-R = Child Depression Rating Scale - Revised; SARS = 
Simpson Angus Rating Scale; BAS = Barnes Akathisia Rating Scale; AIMS = Abnormal Involuntary Movement Scale; 
C-SSRS = Columbia Suicide Severity Rating Scale.


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* All ECGs will be administered at least 3 hours after food intake.
** Subjects should remain fasting for at least 8 hours prior to the baseline visit, Week 6, Week 18, and Week 26..
a.
Baseline Visit is the last visit of the preceding double-blind trial, Study A1281198.  In the case of early termination, all 
procedures specified for Week 26/ET are to be completed. 
b.
Every effort should be made to bring the subject back to the office on the designated study days; however, monthly
office visits will have a 3 day visit window to allow for slight variations in subject schedules.  When scheduling 
subsequent visits, the overall treatment period in the protocol should be maintained.
c.
Subjects who turn 18 years old during the study need to give a written consent.
d.
Only if the subject had clinically significant abnormal findings from a previous visit that require follow-up.
e.
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. 
f.
The subject should be in the sitting position for approximately 5 minutes and in the standing position for approximately 
2 minutes before the measurements are obtained.
g.
Following the baseline visit, unscheduled urine drug screens can be performed at additional visits at the investigator’s 
discretion.
h.
At all required visits, 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 before the subject may receive investigational product. Unscheduled 
pregnancy tests can be performed at additional visits at the investigator’s discretion.  Pregnancy tests should also be 
done whenever one menstrual cycle is missed during the active treatment period (or when potential pregnancy is 
otherwise suspected).  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local 
regulations. 
i.
As double blind study medication will be transitioned during the first two weeks of the study for subjects weighing
>45 kg and during the first week of the study for subjects <45 kg, the investigator or designated staff must be in contact 
with the subject and his/her parent(s) and/or guardian(s) in between the Baseline and Week 1 visit and between the 
Week 1 and Week 2 visit.  After the Week 6 visit, the investigator or designated staff must be in contact with the 
subject and his/her parent(s) and/or guardian(s) in between study visits by telephone to ensure that the subject is taking 
the proper capsules at the proper time and to monitor the tolerability and efficacy of the study medication.
j.
Double-Blind Transition Card provided only to 45 kg weight group subjects.
k.
A risk assessment should be done to determine if it is safe for the subject to participate in the trial or continue to 
participate in the trial, if the subject’s responses during the suicidality assessments indicate that the subject has had 
suicide ideation associated with actual intent and/or plan or exhibited suicidal behaviors. 
l.
Follow up contact will be completed at least 28 calendar days, and up to 35 calendar days after the last administration 
of the investigational product to capture any potential adverse events (see the Time Period for Collecting AE/SAE 
Information section) and to confirm appropriate contraception usage (see the Contraception section).  Contact with the 
subject may be done via a phone call.
m.
Any subject who cannot tolerate the transition study medication during Week 1 should be discontinued from the study.


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1. INTRODUCTION
This protocol describes a 6-month, open label extension study (A1281201) of the 
A1281198 study. The purpose of adding this extension study to the ongoing Geodon 
pediatric bipolar program is to obtain additional longer term safety data in children and 
adolescents with Bipolar I disorder treated with ziprasidone. 
Studies A1281198 and A1281201 are being conducted to fulfill 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 10 to 17 years of age, which was issued 
by the United States (US) Food and Drug Administration (FDA) to Pfizer in August 2004. 
1.1. Mechanism of Action/Indication
Ziprasidone is an atypical antipsychotic with a high affinity for the dopamine D2 receptor 
and the 5-Hydroxytryptamine Receptor 2A (5-HT2A) receptors.  It blocks re-uptake of 
serotonin and norepinephrine and exhibits 5-Hydroxytryptamine Receptor 1A (5-HT1A)
agonist activity.  The indication for this study is pediatric Bipolar I Disorder.  The study will 
include out-patient and/or inpatient, male and female subjects aged 10-17 (inclusive) who 
meet the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM V) 
diagnostic criteria for Bipolar I Disorder (current or most recent episode manic) and who 
participated in Study A1281198.
1.2. Background and Rationale
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 Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), as affirmed 
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 


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stabilizers are FDA approved for this indication.4,6  Among the class of atypical antipsychotic 
medications, risperidone (Risperdal), aripiprazole (Abilify),  quetiapine (Seroquel) and 
olanzapine (Zyprexa) have been approved for the treatment of pediatric bipolar mania.  
Although shown to be effective, several of these 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.
1.2.1. Background on Ziprasidone (CP-88,059-1)
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 a
high 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-HT1A agonist activity may contribute to the alleviation of 
affective and negative symptoms.  Ziprasidone has relatively low affinity for 1 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 P450 3A4 
(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.  An s-NDA (supplemental New Drug Application) 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


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Currently approved and marketed formulations in the US for ziprasidone include the oral 
capsule (20, 40, 60, and 80 mg) and a rapid onset IM (Intramuscular) 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).
Additional information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Brochure.10
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s):
Primary Endpoint(s):

To assess the safety and tolerability of oral 
ziprasidone (20-80 mg BID) during long term, open 
label administration in children and adolescents with 
Bipolar I Disorder who participated in Study 
A1281198.

Safety Assessments;

Adverse event reporting;

Clinical laboratory testing;

Physical examinations;

Blood pressure and pulse;

Height and weight;

Body Mass Index (BMI) and BMI Z score;

Waist circumference;

Electrocardiograms, including QTc;

Special Safety Assessments;

Movement Disorder Scales (SARS, BAS, and 
AIMS);

Columbia Suicide Severity Rating Scale (C-SSRS);

Child Depression Rating Scale (CDRS-R);

Efficacy Assessments;

Young Mania Rating Scale;

Clinical Global Impression of Severity (CGI-S);

Children’s Global Assessment Scale (CGAS).
3. STUDY DESIGN
This 26 week open label extension study is designed to provide information on the safety and 
tolerability of oral ziprasidone (20 to 80 mg BID with meals) during long term administration 
in children and adolescents with Bipolar I Disorder (current or most recent episode manic).  
It will enroll subjects who have participated in the 4 week, double blind, placebo controlled 
safety and efficacy trial, Study A1281198, meet study entry criteria, and wish to receive 
treatment with open label ziprasidone.


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The number of subjects entering this open-label trial will be determined by the number of 
subjects electing to continue treatment after completing or withdrawing from the preceding 
double blind Study A1281198.  We estimate that approximately 55 subjects randomized in 
the double blind study (based on the increased sample size of N=194 subjects) will be 
eligible to continue in this open label extension.  With an expected dropout rate of 
approximately 35%, this gives an estimate of approximately 40 subjects to complete this 
26 week open label study (if all 55 subjects enter the extension study).
The final visit of the double blind trial (Week 4 or early termination visit from A1281198) 
will serve as the Baseline Visit for the extension study.  The first 1-14 days of 
Study A1281201 will be considered a transition period during which the study drug will 
continue to be administered under double-blind conditions. During this double-blind 
transition period, subjects who were on placebo in Study A1281198 will be provided active 
medication that will allow them to be titrated up to the appropriate weight-adjusted target 
dose, following titration schedule that was employed in Study A1281198. Subjects who 
were on active medication (ziprasidone) at the end of Study A1281198 will continue on that 
treatment course under double-blind conditions. At the end of the double-blind transition 
period, all subjects will receive open label ziprasidone.
Any subject who cannot tolerate the transition study medication during Week 1 should 
be discontinued from the study.
After the Week 2 visit for the ≥45 kg subjects and after the Week 1 visit for the <45 kg 
subjects, dosing will be open label and flexible, with dosing adjustments made at the 
discretion of the investigator to maintain optimal efficacy and tolerability.  For subjects with 
a body weight of ≥45 kg, the target dose range is a total daily dose of 120 mg to 160 mg/day 
given in two divided doses with food.  For subjects with a body weight <45 kg, the target 
dose range is a total daily dose of 60 mg to 80 mg/day given in two divided doses with food. 
Subjects who cannot tolerate a dose of 80 mg/day will be allowed to have a dose reduction 
and to continue study treatment at a lower dose that is tolerable to them.  The minimum 
permitted dose is 40 mg/day (20 mg BID) for all subjects.
Post Baseline visits will occur at Weeks 1, 2, 4, 6, 10, 14, 18, 22 and 26 during treatment, 
with a follow up visit at Week 27.
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 Time 
Period for Collecting AE/SAE Information section) and to confirm appropriate contraception 
usage (see the Contraception section).
4. SUBJECT ELIGIBILITY CRITERIA
The following eligibility criteria are designed to select subjects for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular subject is suitable for this 
protocol.


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This study will enroll children and adolescents with Bipolar I Disorder, who have 
participated in double blind Study A1281198.  In order to be enrolled in this open label 
extension trial, subjects must have met the enrollment criteria for Study A1281198, and must
meet the following inclusion and exclusion criteria at the A1281201 extension study Baseline 
visit (last visit in the double blind study).  Any questions regarding eligibility must be 
discussed with a Pfizer clinician prior to the subject’s participation in the study.
Subject eligibility should be reviewed and documented by an appropriate 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.
4.1. Inclusion Criteria
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. The subjects must have received investigational product in Study A1281198 and 
completed at least 3 weeks of double blind treatment before entering this open label 
extension.  However, subjects who have insufficient treatment response and have 
reached their maximum tolerated dose may enroll in the open label extension as early 
as 1 week after the end of their titration.
4. In the investigator’s opinion, the subject must be likely to benefit from antipsychotic 
therapy and must have been free from any clinically significant safety concerns 
during the preceding double blind study (ie, in the opinion of the investigator, the 
benefits that the subject is likely to derive from continued participation must 
outweigh the risks).
5. All fertile male subjects and female subjects of childbearing potential who are 
sexually active and/or their legal guardians, as appropriate, must agree that a highly 
effective method of contraception be used as outlined in this protocol and for the 
duration of the study and for 28 days after the last dose of investigational product. 


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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1.
Any subjects from the preceding double blind trail who experienced a serious adverse 
event which required study medication to be discontinued and the subject to be 
withdrawn from the study. Subjects who experienced cardiac arrhythmias, conduction 
abnormalities, or QTc prolongation (confirmed and persistent Fridericia's correction
(QTcF) >480 msec or increase from baseline QTcF >60 msec) during the preceding 
study.
2. Subjects requiring any medications not allowed by the Concomitant Medication 
Table 12 (see “Concomitant Treatment(s)”).
3. Subjects who require treatment with drugs that are known to consistently prolong the 
QT interval (see Concomitant Medication Table 12).
4. Subjects who are judged by the investigator as being at imminent risk of suicide. 
5. Subjects living in the same home as another study participant or having the same 
caregiver during the same enrollment period (Such subjects can be enrolled in the 
study at different times but may not be in the study at the same time).
6. 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 the C-SSRS
or other information based on the investigator’s judgment indicate:

Suicide ideation associated with actual intent and a method or plan such that a 
positive response (‘Yes’) is made on items 4 or 5 of the suicidal ideation subscale 
of the C-SSRS; or 

Any suicide behaviors such that a determination of ‘yes’ is made to any of the 
suicide behavior items of the C-SSRS.
7. Pregnant female subjects, breastfeeding female subjects.
8. Participation in other studies other than the preceding Study.
9. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior 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.


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4.3. Randomization Criteria
Not applicable.
4.4. Lifestyle Requirements
N/A.
4.4.1. Contraception
All fertile male subjects and female subjects who are of childbearing potential, as applicable 
to the study who are, in the opinion of the investigator, sexually active and at risk for 
pregnancy with their partner(s), 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.  The investigator or his or her designee 
will confirm that the subject has selected an appropriate method of contraception from the list 
of permitted contraception methods (see below).  At time points indicated in the Schedule of 
Activities, the investigator or designee will instruct the subject of the need to use highly 
effective contraception consistently and correctly and document the conversation, and the 
subject’s affirmation, in the subject’s chart.  In addition, the investigator or designee will 
instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject or partner.
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 the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject 
plans to remain 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 separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate. 
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject. 
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of investigational product.


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4.5. Sponsor’s Qualified Medical Personnel
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 product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational product is Ziprasidone Hydrochloride.
5.1. Allocation to Treatment
Throughout most of this study, ziprasidone will be administered as open label (OL) 
investigational product to all subjects. 
However, the dose transition from the double-blind study drug administered in 
Study A1281198 to the open-label dosing in the extension trial A1281201 will be conducted 
under double-blind conditions.
The double-blind dose transition phase of Study A1281201 will comprise Weeks 1 and 2 for 
subjects 45 kg and Week 1 for subjects <45 kg.  The double-blind (DB) medication for this 
transition period will be assigned according to the subject’s randomization number in the 
preceding study so that the investigator remains blinded during this period. 
At the baseline visit of the A1281201 study, subjects will transition onto active medication if 
previously assigned to the placebo group or continue on active study drug.  Over the course 
of the double-blind dose transition period, subjects <45 kg will be transitioned to a total daily 
dose of 60 mg a day by Day 7 of Week 1 and subjects 45 kg will be transitioned to a total 
daily dose of 120 mg a day by Day 10 of Week 2. (Subjects on 160 mg, 140 mg, 100 mg, 
and 80 mg active at the end of Study A1281198 will all be transitioned to 120 mg a day at the 


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end of the two-week transition period. Subjects on 120 mg active at the end of 
Study A1281198 will remain on 120 mg a day through the dose transition period).
Any subject who cannot tolerate the transition study medication during Week 1 should 
be discontinued from the study.
All medication will remain blinded until the end of the transition period.  Diagrams of the 
transition dosing cards for subjects who were on placebo or ziprasidone in Study A1281198 
are provided in Table 1, Table 2, Table 3 and Table 4.
At the end of the double-blind transition period, all subjects will start to receive open label 
ziprasidone.  Diagrams of the double-blind dose transition study drug blister cards are 
provided in Table 1, Table 2, Table 3 and Table 4.
Allocation of subjects to treatment groups will precede through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]).  The site 
personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the subject number.  The site personnel will then be provided with a 
treatment assignment, randomization number, and dispensable unit (DU) or container number 
when investigational product is being supplied via the IRT system.  The IRT system will 
provide a confirmation report containing the subject number, randomization number, and DU 
or container number assigned.  The confirmation report must be signed by two appropriate
staff members and stored in the site’s file.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
5.2. Breaking the Blind
As Applicable.
5.3. Subject 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 (case report form) page should reflect the 
reconciled dose information provided by the subject and/or legal guardian.


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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.
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 5.8).  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. Investigational Product Supplies
5.4.1. Dosage Form and Packaging
All investigational products will be provided by Pfizer and will include oral ziprasidone 
capsules of 20, 40, 60, and 80 mg strength.  Matching placebo capsules may also be supplied 
for the initial 1-14 day dose transition period.  All medication will be packaged in childproof 
blister cards with columns for AM and for PM capsules.
Two different types/designs of child resistant blister cards will be provided over the course of 
the study: a transition card design and a fixed dose card design.  Each transition card will 
contain medication for 7 days plus 3 additional days.  Each fixed dose card will contain
7 days of medication per card plus 1 additional day for use in the open label phase.  During 
the transition phase, all blister cards will have 1 to 2 capsules available for the AM and 1 to
2 capsules for the PM administration. During the open label phase (Weeks 2/3-26), the 
blister cards will have only 1 capsule available for the AM and 1 capsule available for the 
PM dose of active medication.  Each of the AM or PM columns will contain a 20 mg, 40 mg, 
60 mg or 80 mg ziprasidone capsules (or matching placebo) during the transition and only 
active ziprasidone capsules during open-label treatment. The target dose ranges for subjects 
<45 kg is 60 to 80 mg/day and for subjects 45 kg, 120 to 160 mg/day, which are identical to 
the target dose ranges used in study A1281198.
For more information please refer to the Investigational Product manual for all items related 
to IP. 
Dose Transition Card Container Types
Double-Blind Dose Transition Card
Active Ziprasidone or Placebo 
(separate cards for Day 1/Baseline 
and Week 2/Visit 2)
45 kg body weight
Active Ziprasidone or Placebo 
(Day 1/Baseline)
<45 kg body weight


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In order to accommodate the flexible dosing permitted by the protocol following the dose 
transition period, 7 types of open label fixed dosing cards, each with a different total daily
dose of study drug as described in below tables:
Fixed Dose OL 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
5.4.2. Preparation and Dispensing
On Day 1 (Baseline Visit), one transition card will be dispensed based on the subject’s 
weight (45 kg or <45 kg) and previously assigned treatment in Study A1281198 for the first 
week of dosing.  Only subjects 45 kg will receive a transition card at Week 2 if needed.
After Week 1, subjects from the <45 kg group will be provided a fixed dose card for the 
second week of the dose transition phase. Medication dose- and weight-based tables 
illustrate the dosing sequence subjects will be assigned during the transition periods by 
weight and current assigned dose in A1281198 (Table 1, Table 2, Table 3 and Table 4).
Patients <45 kg will be assigned a 60 mg active/placebo titration card at Day 1 of A1281201. 
Patients ≥45 kg will be assigned one of three dose levels: Patients on the 80 mg or 100 mg 
dose level in A1281198 will be given a 100 mg active/placebo titration card Day 1 of 
A1281201, Patients on the 120 mg dose level in A1281198 will be given a 120 mg 
active/placebo titration card Day 1 of A1281201, and Patients on the 140 mg or 160 mg dose 
level in A1281198 will be given a 140 mg active/placebo titration card Day 1 of A1281201. 
After the baseline visit, the investigator or designed staff must be in contact with the subject 
and his/her legal guardian(s) on at least one occasion between the baseline visit and the 
Week 1 visit and between the Week 1 visit and the Week 2 visit, 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 and efficacy of the titration plan.
After the Week 6 visit, the investigator or designated staff must be in contact with the subject 
and his/her parent(s) and/or guardian(s) in between study visits by telephone to ensure that 
the subject is taking the proper capsules at the proper time and to monitor the tolerability and 
efficacy of the study medication.


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Table 1.
Double-Blind Dose Transition Blister Cards for 45 kg Subjects on 
160 mg/day or 140 mg/day of Active Ziprasidone or Placebo at End of Study 
A1281198, Weeks 1 and 2
140 mg Week 1 Active Titration Card
140 mg Week 1 Placebo Titration Card
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
80
140/160*
1
20
20
2
60
80
140
2
20
20
40
3
60
80
140
3
20
20
40
4
60
80
140
4
20
40
60
5
60
80
140
5
20
40
60
6
60
80
140
6
40
40
80
7
60
80
140
7
40
40
80
8
60
80
140
8
40
40
80
* Subjects on a dose of 160 mg at the end of the A1281198 study will remain at that dose for 1 additional day 
during the transition period due to the Day 1 card PM dose design. Starting on Day 2 of the transition period 
these subjects will receive a total daily dose of 140 mg/day.
120 mg Week 2 Active Titration Card
120 mg Week 2 Placebo Titration Card
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
60
120
1
40
60
100
2
60
60
120
2
40
60
100
3
60
60
120
3
60
60
120
4
60
60
120
4
60
60
120
5
60
60
120
5
60
60
120
6
60
60
120
6
60
60
120
7
60
60
120
7
60
60
120
8
60
60
120
8
60
60
120
Table 2.
Double-Blind Dose Transition Blister Cards for 45 kg Subjects on 
120 mg/day of Active Ziprasidone or Placebo at End of Study A1281198, 
Weeks 1 and 2
120 mg Week 1 Active Titration Card
120 mg Week 1 Placebo Titration Card
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
60
120
1
20
20
2
60
60
120
2
20
20
40
3
60
60
120
3
20
20
40
4
60
60
120
4
20
40
60
5
60
60
120
5
20
40
60
6
60
60
120
6
40
40
80
7
60
60
120
7
40
40
80
8
60
60
120
8
40
40
80


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120 mg Week 2 Active Titration Card
120 mg Week 2 Placebo Titration Card
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
60
60
120
1
40
60
100
2
60
60
120
2
40
60
100
3
60
60
120
3
60
60
120
4
60
60
120
4
60
60
120
5
60
60
120
5
60
60
120
6
60
60
120
6
60
60
120
7
60
60
120
7
60
60
120
8
60
60
120
8
60
60
120
Table 3.
Double-Blind Dose Transition Blister Cards for 45 kg Subjects on 
80 mg/day or 100 mg of Active Ziprasidone or Placebo at End of 
Study A1281198, Weeks 1 and 2
100 mg Week 1 Active Titration Card
100 mg Week 1 Placebo Titration Card
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
60
100*
1
20
20
2
40
60
100
2
20
20
40
3
40
60
100
3
20
20
40
4
40
60
100
4
20
40
60
5
40
60
100
5
20
40
60
6
40
60
100
6
40
40
80
7
40
60
100
7
40
40
80
8
40
60
100
8
40
40
80
* Subjects who were assigned 80 mg at the end of Study A1281198 will have a 20 mg increase in dose starting 
on Day 1 of the double blind transition period due to the design of the transition dose card. 
120 mg Week 2 Active Titration Card
120 mg Week 2 Placebo Titration Card
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
60
60
120
1
40
60
100
2
60
60
120
2
40
60
100
3
60
60
120
3
60
60
120
4
60
60
120
4
60
60
120
5
60
60
120
5
60
60
120
6
60
60
120
6
60
60
120
7
60
60
120
7
60
60
120
8
60
60
120
8
60
60
120


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Table 4.
Double Blind Dose Transition Blister Cards for <45 kg Subjects on 
40 mg/day, 60 mg/day, or 80 mg of Active Ziprasidone or Placebo at End of 
Study A1281198, Week 1
60 mg Week 1 Active Titration Card
60 mg Week 1 Placebo Titration Card
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily Dose 
(mg)
1
40
60/80*
1
20
20
2
20
40
60
2
20
20
40
3
20
40
60
3
20
20
40
4
20
40
60
4
20
20
40
5
20
40
60
5
20
40
60
6
20
40
60
6
20
40
60
7
20
40
60
7
20
40
60
8
20
40
60
8
20
40
60
* Subjects who were assigned 40 mg at the end of Study A1281198 will have a 20 mg increase in dose starting 
on Day 1 of the double blind transition period due to the design of the transition dose card. Subjects who were 
assigned 80 mg at the end of Study A1281198 will receive 80 mg on Day 1 of the dose transition week but from 
Day 2 onwards will receive a total daily dose of 60 mg/day. 
Subjects weighing <45 kg should be issued an open label, fixed dosing card with the desired 
total daily dose for the second week of the dose transition phase(ie, either 40 mg/day, 
60 mg/day, or 80 mg/day; see Table 5, Table 6, or Table 7).
The investigator will decide which fixed dose blister card to provide to the subject for the 
following week, based on clinical judgment.
Table 5.
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


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Table 6.
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
Table 7.
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
Subjects weighing 45 kg should be issued an open label fixed dosing card with the desired
total daily dose at the start of the third week (Day 15) of the extension study (ie, either 
80 mg/day, 100 mg/day, 120 mg/day, 140 mg/day or 160 mg/day total daily dose; see
Table 8-Table 11.
Table 8.
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


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Table 9.
120 mg Fixed Dose Regimen
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily 
Dose 
(mg)
1
60
60
120
2
60
60
120
3
60
60
120
4
60
60
120
5
60
60
120
6
60
60
120
7
60
60
120
8
60
60
120
As a reminder subjects weighing 45 kg could be provided the 140 or 160 mg/day fixed dose 
card (see Table 10 and Table 11) only if they have tolerated 120 mg/day; in addition, the 
140 and 160 mg/day fixed dose card should not be issued before Day 15 of the study.
Table 10.
140 mg Fixed Dose Regimen
Day
AM Dose 
(mg)
PM Dose 
(mg)
Total Daily 
Dose 
(mg)
1
60
80
140
2
60
80
140
3
60
80
140
4
60
80
140
5
60
80
140
6
60
80
140
7
60
80
140
8
60
80
140
Table 11.
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


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Only site personnel according to their role as determined on the site delegation log may 
dispense investigational product cards. Subjects will be instructed to take medication with 
food and to take one capsule in the AM and one capsule in the PM from each assigned blister 
card during the open label phase.
The investigational product will be dispensed using an IRT drug management system at each 
visit from baseline to Week 22.  A qualified staff member will dispense the investigational 
product, a unique container numbers on the blister cards provided, in quantities appropriate 
for the study visit schedule.  The subject/caregiver should be instructed to maintain the 
product in the blister cards, as provided throughout the course of dosing and return the blister 
cards, to the site at the next study visit.
5.5. Administration
As study drug administration is complex, the parent or guardian should closely supervise 
dosing throughout the study, especially during the transition period. Depending on the
assigned investigational product, 1 to 2 capsules are taken in the morning and 1 to 2 capsules
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.
The missed dose should be skipped if <4 hours remain to the next scheduled dose. 
All investigational product is to be taken with food and approximately 12 hours apart.  
Capsules are to be taken intact.  Swallow the capsule whole.  Do not crush or chew the 
capsule.
Transition Period:
The target dose ranges for subjects <45 kg is 60 to 80 mg/day and for subjects 45 kg, 
120 to 160 mg/day, which are identical to the target dose ranges used in Study A1281198.
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 to 160 mg/day.  A dose of 160 or 140 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.
Any subject who cannot tolerate the transition study medication during Week 1 should 
be discontinued from the study.
Open-Label Weeks 3-26
After the Week 2 visit for the ≥45 kg subjects and after the Week 1 visit for the <45 kg 
subjects, dosing will be open-label and flexible, with dosing adjustments made at the 
discretion of the investigator to maintain optimal efficacy and tolerability.  Subjects who 
cannot tolerate a dose of 80 mg/day will be allowed to have a dose reduction and to continue 
study treatment at a lower dose that is tolerable to them.  The minimum permitted dose is 
40 mg/day (ie, 20 mg BID) for all subjects. The site will dispense 2 blister cards to the 


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patient at the Week 2 and Week 4 visit. From the Week 6 visit onwards, there will be 
4 weeks between each visit and the site will dispense 4 blister cards to the patient at each 
visit.  Blister cards for Weeks 3-26 will each contain medication for 7 days plus 1 additional 
day. All investigational products will be provided by Pfizer and will include oral ziprasidone 
capsules of 20, 40, 60, and 80 mg strength.  Matching placebo capsules will also be supplied 
for the initial tapering period. All medication will be packaged in childproof blister cards 
with columns for AM and for PM capsules (see Dosage Form and Packaging section).
Dose Reductions
If a subject with a body weight 45 kg cannot tolerate the target dose of 120–160 mg/day 
during the open label phase (Weeks 3-26) the investigator can reduce the dosage. In general, 
it is recommended dose reductions not exceed 40 mg/day and occur only once a week unless 
a subject is experiencing an adverse event that necessitates a faster dose reduction.
If a subject weighing <45 kg cannot tolerate the target dose of 60-80 mg/day during the open 
label phase (Weeks 3-26), the investigator can reduce the total daily dosage to 40 mg/day.
Any subject who cannot tolerate a minimum dose of 40 mg/day will be discontinued 
from the study.
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 Principal Investigator (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).
5.6. Summary of the Dose Titration Schedule for Study A1281201
1. No dose adjustments are allowed during Week 1 of the Dose Transition period (for 
either the <45 kg or 45 kg dose category); subjects who cannot tolerate the Week 1 
dose titration should be withdrawn from the study.
2. Weekly dose adjustments (increases or decreases) are allowed from Week 2 of the 
Dose Transition period to the end of the study (Week 26).  In general, dose 
adjustments should not occur more frequently than every 7 days to provide an 
adequate period of time to evaluate the clinical effect of the dose adjustment. Dose 
adjustments are achieved by issuing an open label fixed dosing card to the subject (ie, 
with a total daily dose of 40 mg, 60 mg, 80 mg, 100 mg, 120, 140 mg, or 160 mg).
3. The dose may be increased if the subject has been tolerating the current dose level 
without significant side effects; but, in the clinical judgment of the investigator, has 
had an insufficient clinical efficacy response. The clinical rationale for the dose 
increase should be documented in the source documentation for the subject. 


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4. In general, dose increases should not exceed 20 mg. However, subjects weighing 
45 kg may be increased to 140 mg or 160 mg total daily dose if they have tolerated 
the 120 mg dose well, have reached Day 15 of the study, and have had an insufficient 
clinical efficacy response to the 120 mg total daily dose.
5. The dose may be decreased if, in the clinical judgment of the investigator, the subject 
is not tolerating the current dose well and is likely to benefit from continued treatment 
with a lower dose of study drug that may be better tolerated.  There is no limit on the 
number of dose decreases; however, subjects who cannot tolerate a minimum total 
daily dose of 40 mg should be withdrawn from the study. The clinical rationale for the 
dose decrease should be documented in the source documentation for the subject.  In 
general, dose decreases should not exceed 40 mg.
6. Subjects who, in the clinical judgment of the investigator, have reached their 
maximum tolerated dose and still have an insufficient clinical response should be 
withdrawn from the study.
5.7. Investigational Product Storage 
The investigator or an approved representative (eg, pharmacist), will ensure that all 
investigational product is stored in a secured area with controlled access under required
storage conditions and in accordance with applicable regulatory requirements. 
Investigational products should be stored in their original containers and in accordance with 
the labels.  Investigational product is to be stored at 15-25C (59-77F). 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 


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Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products. 
5.8. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.  All blister cards of study drug must 
be returned to the investigator by the subject at every visit and at the end of the trial.
5.8.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.9. Concomitant Treatment(s)
The Concomitant Medication Table that follows lists common concomitant medications that 
are permitted or prohibited during the study, however this list may not be fully inclusive.  
Subjects will 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 
investigator must record the use of all concomitant medications in the eCRF (electronic Case 
Report Form).
The chronic use of certain medications (some hormones, antihypertensives, diuretics, and 
oral hypoglycemic) is allowed if the subject was using these medications during the 
preceding double-blind study at a stable dose and the subject’s condition is stable.
Lorazepam may be used PRN (as necessary) up to 2 mg/day for anxiety or agitation during 
the first 4 weeks of dosing but should not be given within 6 hours prior to assessments being 
performed.  If possible, the investigator should start with a low dose of lorazepam to control 
a subject’s symptoms and increase incrementally up to a total of 2 mg, 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.  


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The frequency and dose of benzodiazepine administration will be recorded on the eCRF.  For 
treatment of insomnia lorazepam may be used as specified above, or alternatively 
diphenhydramine or zolpidem are permitted.
Urine drug screening (UDS) will be performed at the baseline visit (last visit in the 
double-blind study) and at visits for Weeks 6 and 26 (or early termination), and at any other 
visit deemed necessary by the investigator.  Subjects with a positive UDS (amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, methaqualone, opiates, 
phencyclidine or propoxyphene) should be counseled against the use of these substances and 
should be told the implications of drug use for study participation, and his/her parents or 
guardians should be notified. However, a positive UDS will not automatically result in 
exclusion or discontinuation from the study.  In the case of subjects with a positive UDS 
(other than for occasional cannabinoid use), investigators should consult with the Sponsor to 
determine if appropriate to continue the subject in the study.
Table 12.
Prohibited/Concomitant Medication Table
The following agents are prohibited during the trial and must be discontinued at least 4½ 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, 
lisdexamfetaminedimesylates, methamphetamines, and methylphenidates);
Antidepressants (see mono amine 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);
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.
Biotin (dose exceeding 100mcg daily) Children multivitamin levels allowed.


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The following medications are cited in the Exclusion criteria (A1281198) 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 investigational product:
Antihypertensives;
Antianginal agents;
Antiarrhythmics (except QTc prolonging);
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 antiinflammatory 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
Every effort should be made to bring the subject back to the office on the designated study 
days; however, monthly office visits will have a 3 day visit window to allow for slight 
variations in subject schedules.  When scheduling subsequent visits, the overall treatment 
period in the protocol should be maintained. 
6.1. Baseline Visit
The Baseline visit for this open-label extension study is the same visit as the end of treatment 
visit in the preceding double-blind study.  Procedures to be completed at this visit are 
detailed in the A1281198 protocol and are indicated on the Schedule of Activities in this 
protocol.  At this visit, the investigator must confirm that the subject meets all inclusion and 
exclusion criteria for the extension study, and should carefully assess all medical and 
non-medical conditions in deciding whether the study is appropriate for a particular subject.


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Entry into the open-label study requires informed consent in addition to that already obtained 
for the double-blind study.  The subject and the authorized legal representative must 
understand the nature of the extension study and be able to comply with protocol 
requirements.  The representative must sign an Informed Consent Document and the subject 
must provide Written Assent prior to any study-specific procedures being performed.  The 
person obtaining the consent must be sufficiently trained on medical issues so that questions 
can be adequately addressed; therefore, this person must be an M.D., Ph.D. or RN (persons 
without one of these degrees must be approved by Pfizer). Any subject who turns 18 years of 
age during the study will need to provide written consent.
Investigational product for the first week of treatment will be dispensed according to the 
weight-based dose transition scheme described previously (see Section 5.5).  Study drug
administration will be carefully explained to the subject and legal guardian (see details in 
Section 5.5, Study Drug Administration).  As double-blind investigational product will be 
transitioned during the first and second weeks (Week 1 only for subjects weighing <45 kg) of 
the study and open-label medication will be transitioned in, the investigator or designated 
staff must be in contact with the subject and his/her parent(s) and/or guardian(s) at least once
a week during the first two weeks of the study, 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 
and efficacy of the transition plan. After the Week 6 visit, the investigator or designated staff 
must be in contact with the subject and his/her parent(s) and/or guardian(s) in between study 
visits by telephone to ensure that the subject is taking the proper capsules at the proper time 
and to monitor the tolerability and efficacy of the study medication.
6.2. Study Visits During Open-label Treatment
Subjects will attend study visits at Weeks 1, 2, 4, 6, 10, 14, 18, 22, and 26 (or early 
termination). There will also be a brief follow-up (off treatment) visit at Week 27. The 
following will be assessed or administered at EVERY on-treatment visit:

Adverse events;

Review of concomitant medications;

Blood pressure and pulse;

Drug accountability (Document drug returned and record any dosage changes, 
except Day 1);

Dispense study drug (except Week 26 or early termination);

Double-blind transition card provided only for 45 kg weight group subjects 
(Week 1);

CGI-S;

C-SSRS;


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
CDRS-R;

Movement disorder scales (SARS, BAS, AIMS);

A urine pregnancy test will be obtained on all female subjects at all study visits.  A 
positive urine pregnancy test should be confirmed with a serum pregnancy test.

Verification of contraception.
At week 4 in addition to the above the following will be assessed or administered:

Electrocardiogram.
At Weeks 1, 2, 6, 14, 22 and 26 (or early termination), in addition to the above, the following 
will be assessed or administered: 

YMRS;

Electrocardiogram.
At Weeks 6 and 26 (or early termination), in addition to the above, the following will be 
assessed or administered:

Clinical laboratory tests (chemistry, hematology, urinalysis) and urine drug screen;

Body weight, height, BMI, BMI z score, and waist circumference;

Hormones (free T4 & TSH (thyroid stimulating hormone), Prolactin).
At Weeks 6, 18, and 26 (or early termination), in addition to the above, the following will be 
assessed or administered:

Fasting glucose, lipid profile, insulin and glycated hemoglobin (HbA1c).
The following will be done only at Week 26 (or early termination):

Physical exam;

CGAS.
A urine pregnancy test will be obtained on all female subjects at all study visits.  A positive 
urine pregnancy test should be confirmed with a serum pregnancy test.
Following the baseline visit, unscheduled urine drug screens can be performed at additional 
visits at the investigator’s discretion.


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Since no investigational product will be available after the Week 26 visit, the physician may 
initiate appropriate treatment with commercially available medications.
A Telephone Contact is required between the study staff and the subject and his/her parent(s) 
and/or guardian(s) to ensure that the subject is taking the proper capsules at the proper time 
and to monitor the tolerability and efficacy of the study drug.  The telephone contact will 
occur as follows:

Between the Baseline and Week 1 visit;

Between the Week 1 and Week 2 visit;

Between the monthly visits starting after the Week 6 visit (contact will occur at 
approximately Week 8, 12, 16, 20, 24).
6.3. Follow-up Visit
Subjects will attend a brief follow-up visit at Week 27 (or one week after the 
end-of-treatment visit, in case of early termination).  At this visit, adverse events and 
concomitant medications will be documented.  The CSSR-S will be performed, verification 
of contraception will be assessed, and a urine pregnancy test will be obtained on all female 
subjects. 
The following should be done ONLY IF a subject had abnormal findings at a previous visit 
that require follow-up: body weight/BMI, height, BMI Z-score, waist circumference; 
electrocardiogram (ECG); blood pressure/pulse; clinical laboratory values
(chem/hemato/urinalysis); hormones (free T4, TSH, Prolactin), fasting glucose, lipid profile,
insulin, and HbA1c; movement disorder scales (SARS, BAS, AIMS) and CDRS-R.  A urine 
pregnancy test will be obtained on all female subjects at the follow-up visit.
Follow up Contact
Follow up contact will be completed at least 28 calendar days, and up to 35 calendar days 
after the last administration of the investigational product to capture any potential adverse 
events (see the Time Period for Collecting AE/SAE Information section) and to confirm 
appropriate contraception usage (see the Contraception section).  Contact with the subject 
may be done via a phone call.
Certain adverse events will result in mandatory withdrawal from the study after appropriate 
safety follow up.
6.4. Subject Withdrawal
Subjects may withdraw from the trial 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 (see also the 
Withdrawal From the Study Due to Adverse Events section), 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.


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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 
the Pfizer clinical monitor or his/her designated representative.  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 8.4.4.
An early termination visit must be scheduled for any subject who discontinues early from the
study.  At this visit, all assessments scheduled for the Week 26 visit (9) 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).
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.
Certain adverse events will result in mandatory withdrawal from the study after appropriate 
safety follow-up. 
These are as follows:
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.


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Event
Criteria
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 (Bazett’s correction) prolongation 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.  
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. 
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 who cannot tolerate a minimum of 40 mg/day of ziprasidone.


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Event
Criteria
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 Week 26 according to the Schedule of Activities
should be followed.
Rescue 
Medications
Subject requiring concomitant treatment with mood stabilizers, 
antidepressants, or stimulants.
Withdrawal of consent:
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing
status. This includes follow-up with persons authorized by the subject as noted above. Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.


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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 that 
he or 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 manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety Assessments
7.1.1. Adverse Events
Adverse events will be assessed and documented on the eCRF at every visit.  Detailed 
instructions for adverse event reporting are found in Section 8 below.
7.1.2. Clinical Laboratory Testing
The results of all laboratory tests required by the protocol will be recorded electronically.  A 
central laboratory will be used for most laboratory tests.  Detailed instructions on the 
handling of laboratory samples will be provided by the Central Laboratory.  The instructions 
will include guidance on cooling of samples following collection, on centrifugation, and on 
preparation for shipping.
Subjects should remain fasting for at least 8 hours prior to the Baseline, Week 6, 18, and 
Week 26 lab samples, because of the assessment of a lipid profile and insulin levels.  The 
fasting/non fasting condition will be documented.
The following tests, requiring the drawing of approximately 20 mL of blood, will be 
completed at the Baseline visit and at Weeks 6 and 26 (or early termination):

Hematology (complete blood count with differential % and absolute and platelet 
counts);

Blood chemistry (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
(BUN), creatinine, glucose, calcium, inorganic phosphorus, magnesium, Serum 
glutamic oxaloacetic transaminase (SGOT) [aspartate aminotransferase (AST)], 
Serum glutamic pyruvic transaminase (SGPT) [alanine aminotransferase (ALT)],
LDH (lactate dehydrogenase), (total bilirubin, albumin, and total protein);

Hormones (free T4 and TSH, Prolactin);


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
For female subjects, a urine pregnancy test should be performed followed by a serum 
pregnancy test if the urine test is positive;

Urinalysis.
The following tests will be done at the Baseline visit (last visit in Study A1281198) and at 
Weeks 6, 18 and 26 (or early termination):

Fasting glucose, lipid profile (cholesterol total, high density lipoprotein (HDL), 
Low-density lipoprotein (LDL)], triglycerides), insulin and HbA1c.
Subjects should remain fasting for at least 8 hours prior to these lab samples.  The 
fasting/non fasting condition will be documented.
The following test will be done in female subjects at the baseline visit and all post-baseline 
visits (including any ET (Early Term) visit and the Follow Up visit):

Urine pregnancy test (a positive urine pregnancy test should be confirmed by a serum 
pregnancy test).
In addition to the scheduled tests, serum pregnancy tests and urine drug screening may also 
be administered at any other visit that the investigator deems necessary.
No routine laboratory assessments will be performed at the follow-up visit (Week 27) except 
redraws for laboratory abnormalities present at a previous visit.
Abnormal test findings should be followed up appropriately and reported as an adverse event 
according to the criteria summarized in Section 8.
7.1.3. Physical Examinations
Physical examinations are to be performed at the Baseline visit (last visit in 
Study A1281198) and at Week 26 (or early termination).  Any significant physical 
examination finding should be recorded as an adverse event.
7.1.4. Blood Pressure and Pulse
Blood pressure will be measured in the dominant arm (as defined by the subject, parent or 
legal guardian) and recorded to the nearest whole numbers.  Pulse rate will be measured for 
at least 30 seconds.  Two measurements will be obtained at each visit: once while the subject 
is in a sitting position and then in a standing position to assess orthostatic effects.  The 
subject should be in the sitting position for approximately 5 minutes and in the standing 
position for approximately 2 minutes before the measurements are obtained.


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7.1.5. Body Weight and Height, BMI, Waist Circumference
Body weight, height, and waist circumference will be measured at the Baseline visit and at 
Week 6 and 26 (or early termination).  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.  Investigators will
calculate the subject’s Body Mass Index (BMI) from height and weight.  A BMI and BMI 
z-score calculator will be provided within the Firecrest site.
BMI z-score 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 in the 
subject’s eCRF. All BMI calculations are to be recorded by the investigator in the source 
documents and eCRF.
7.2. Electrocardiograms
A 12-lead ECG will be obtained from each subject at Weeks 1, 2, 4, 6, 14, 22 and Week 26
and repeated at the follow-up visit if abnormalities were present at the Week 26 (or early 
termination) visit.  Baseline ECG data will be obtained from A1281198 final study visit. 
The subject must fast at least 3 hours before ECGs are obtained.  ECGs must be obtained 
prior to the collection of any blood sample because drawing blood 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.
All ECGs must be reviewed for safety at the site by a physician qualified to read and 
interpret the results (ie, a pediatric cardiologist, or an adult cardiologist experienced in the 
interpretation of pediatric ECGs should be contacted to discuss the ECG). This assessment 
will include the calculation of QTcF.  ECGs must be reviewed on the day of the recording, 
signed and dated by the reader, and retained in the subject’s study records.
ECGs in this study will be collected with an ECG recorder to be supplied to the site.  This 
machine can generate a hard copy tracing, as well as digitally transmit via a modem to a 
central ECG service (BMS- BioMedical Systems).  Standardized site and subject 
identification information have to be entered into the machine by the ECG technician prior to 
each recording.  The electronic version transmitted to BMS will be the same as the hard 
copy.  BMS will provide clinical interpretation and overread designated parameters (Heart 
Rate (HR), PR, Respiration Rate (RR), QRS QT, QTcF, QTcB).
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.


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7.3. Special Safety Assessments
7.3.1. Child Depression Rating Scale – Revised (CDRS-R)
The Child Depression Rating Scale – Revised11 (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 years of age, it has been widely used with adolescents 
and its developers recommend it for both children and adolescents.12 Clinicians’ ratings are 
based on information obtained from interviews with both child and parent (or guardian) 
informants; 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 minutes 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 as a safety measure to monitor subjects for the 
onset of a depressive episode.  The CDRS -R will be completed at every visit except baseline 
(Baseline data will be carried over from Study A1281198).
7.3.2. Movement Disorder Scales
The following scales will be used to assess symptoms and findings related to Parkinsonism, 
akathisia, and abnormal involuntary movements.  The scales will be administered at each 
visit.  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.
7.3.2.1. Simpson-Angus Rating Scale (SARS)
The Simpson-Angus Rating Scale13 (SARS) will be administered by investigators 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.


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7.3.2.2. Barnes Akathisia Rating Scale (BAS)
The Barnes Akathisia Rating Scale14 (BAS) will be administered by investigators 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.
7.3.2.3. Abnormal Involuntary Movement Scale (AIMS)
The Abnormal Involuntary Movement Scale15 (AIMS) will be used to document occurrences 
of dyskinesias in subjects, specifically tardive dyskinesia.  The scale incorporates observation 
and brief examination of the subject by the investigator 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.
7.3.2.4. Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia Suicide Severity Rating Scale (C-SSRS)16 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.17  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 
Central nervous system (CNS) and non CNS indications.


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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 10-11 at the Screening Visit (A1281198), 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.
For subjects who are ages 12-17 at the Screening Visit (A1281198), the Since Last Visit 
version of the C-SSRS should be utilized (A1281198 study).  The Since Last Visit version 
refers to the subject’s experience since their last visit.
A risk assessment should be done to determine if it is safe for the subject to participate in the 
trial or continue to participate in the trial, if the subject’s responses during the suicidality 
assessments indicate that the subject has had suicide ideation associated with actual intent 
and/or plan or exhibited suicidal behaviors.
7.4. Efficacy Assessments
7.4.1. 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 Behavior, Appearance and Insight.  It has 


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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, and will be 
administered at Weeks 1, 2, 6, 14, 22 and 26.
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.18,19
The YMRS must be administered by an appropriately qualified and experienced individual 
who has been certified through the Pfizer rater training program.  For each subject, the same 
rater should administer the YMRS at each of the indicated time points.
7.4.2. Clinical Global Impression of Severity Scale (CGI-S)
The Clinical Global Impression of Severity (CGI-S) Scale20 is a standardized assessment tool 
used to rate the severity of a subject’s illness.  The CGI-S assesses the investigator’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-S will be administered at every study visit except 
the follow-up visit.
7.4.3. Children’s Global Assessment Scale 
The Children’s Global Assessment Scale21 (CGAS) is a clinician-rated global assessment 
item for children based on symptoms and social functioning in home, school, and community 
settings.  Scores on this single item range from 1-100 (higher levels indicate greater health), 
with descriptive anchors for every 10-point interval.  Scores above 70 on this scale are 
considered within the “normal” range.  The CGAS will be completed at week 26 or early 
termination.
7.5. Pregnancy Testing
For female subjects of childbearing potential, 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 confirmed pregnancy test, the subject will be withdrawn from investigational 
product administration of investigational product but may remain in the study.  Pregnancy 
tests may also be repeated as per request of Institutional Review Board (IRB) / Ethics 
Committee (EC) s or if required by local regulations.


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7.6. Rater Qualifications/Training/Certification for Diagnostic, Efficacy, and Safety 
Rating Scales 
For this study, a central CRO (Contract Research Organization) will work with the Sponsor 
to verify that raters meet the rating scale qualification criteria for the study and are trained on 
administration of the scales.  This will apply to raters identified at the start of the study as 
well as those raters that may need to be added during the life of the study.
Potential raters who fully meet the education and clinical experience described in Appendix 2
will be allowed to continue with rater training without Sponsor review.  Potential raters who 
do not fully meet these criteria will require individual review by the central CRO and the 
Sponsor for potential inclusion in rater training.  A final determination will be made by the 
Sponsor as to whether the potential rater can or cannot proceed to training.
When a rater has been approved based upon their education and experience as described 
above, they will be granted access to the study specific training materials.  Once all scale 
specific training is satisfactorily completed, documentation of training completion by the 
central CRO will occur.  Upon receipt of the documentation by the central CRO, a rater can 
begin administration of the specific scale(s) for the study.
If a rater has been approved to rate in Study A1281198 they will be allowed to rate the same 
scales for this study.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)


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All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information. This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and 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 Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE 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.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.


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8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject, parent or legally acceptable representative.  In addition, each 
study subject, parent or legally acceptable representative will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days; except as indicated below after the last administration of the 
investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
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.


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8.1.5. 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 on the CRF, and report such 
an assessment in accordance with the SAE 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.  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 that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions will be carried out in 
accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study 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 signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;


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
Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

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 (outside of any protocol-specified dose 
adjustments) 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 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event 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;

Results in persistent or significant disability/incapacity (substantial disruption of the 
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
Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
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.
8.2.4. 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 is 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).
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 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);


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
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;

Preplanned 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 noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, 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 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol specified SAEs in this study.  All SAEs will be reported to Pfizer 
safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database.


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8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a subject 
presents with clinical signs/symptoms, such LFT results should be managed and followed as 
described below.
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (Tbili) elevations (>2 × ULN) by several days 
or weeks.  The increase in Tbili typically occurs while AST/ALT is/are still elevated above 
3 × ULN (ie, AST/ALT and Tbili values will be elevated within the same lab sample).  In 
rare instances, by the time Tbili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to Tbili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and Tbili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a Tbili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For subjects with baseline AST OR ALT OR Tbili values above the ULN, the
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).


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
Preexisting values of Tbili above the normal range: Tbili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and Tbili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator 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 and Tbili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
Tbili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.


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8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

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.

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).

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 subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE 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) to Pfizer Safety 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).
Follow-up is conducted to obtain general information on the 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 Safety 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.


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Additional information about pregnancy outcomes that are reported to Pfizer Safety 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 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  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 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.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. 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 Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors and Lack of Efficacy
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors and lack of efficacy.


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors and lack of 
efficacy
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

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.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4.4.2. Lack of Efficacy 
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summarization of the data collected in this trial will be 
documented in a Statistical Analysis Plan (SAP). The SAP may modify the plans outlined in 
the protocol; however, any major modifications of significant change to the primary endpoint 
definition and/or its or analysis will also be reflected in a protocol amendment.
As this is an open label study with no comparator, no inferential statistics will be performed.
Quantitative variables will be described by standard descriptive statistics (n, mean, standard 
deviation, minimum, and maximum, 95% confidence intervals), and qualitative variables will 
be summarized by frequency tables.  Summaries will include data for all subjects who took at 
least one dose of investigational product in this open label extension study.


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Baseline values for efficacy, outcomes and special safety endpoints will be the last 
observation made prior to the subject receiving open label treatment.  For safety, for those 
subjects who were randomized to placebo in the double blind study, baseline values will be 
the last (pre dose, for ECG and blood pressure/pulse only) observation prior to initiating 
dosing in the open label extension study normally, the (pre dose, for ECG and blood 
pressure/pulse only) observation of the last visit in the double-blind study; and for those 
subjects who were randomized to ziprasidone in the double blind study, baseline values will 
the last observation prior to initiating dosing in the double blind study (normally, the value 
from the Baseline visit in the double blind study).
9.1. Sample Size Determination
The number of subjects entering this open-label trial will be determined by the number of 
subjects electing to continue treatment after completing or withdrawing from the preceding 
double-blind Study A1281198.  We estimate that approximately 55 subjects randomized in 
the double-blind study (which is proposed to have the sample size increased to 
N=194 subjects) will be eligible to continue in this open label extension.  With an expected 
dropout rate of approximately 35%, this gives an estimate of approximately 40 subjects to 
complete this 26 week open label study (if all 55 subjects enter the extension study).
9.2. Efficacy Analysis
No formal efficacy or outcomes analyses will be performed for this study.  However, data on 
the YMRS, CGI-S, and CGAS will be summarized using descriptive statistics as described 
above.
9.3. Safety Analysis
The safety assessments include:

Adverse event reporting, [including Possibly Suicide Related Adverse Events 
(PSRAEs)];

Clinical laboratory values;

Physical Exams;

Vital signs (blood pressure, pulse rate);

Weight, height, BMI, BMI Z-score, waist circumference;

Electrocardiograms;

No formal statistical analysis will be conducted on any of the above safety data.
Data for height, weight, BMI, and waist circumference will be summarized by time point
using descriptive statistics.  Additionally, height, weight, and BMI will be standardized using 
CDC (Child Development Chart) growth charts and the resulting z scores presented in 


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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 antipsychotic treatment will be 
included in the safety data summarization.  All adverse events that are observed from the 
time of first dosing with open label investigational product until the end of study 
participation will be included in data summaries.
All adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities. The incidence of treatment emergent adverse events will be tabulated by system 
organ class.  The incidence of treatment emergent adverse events will be displayed by 
severity and attribution.  In addition, the incidence of serious adverse events and adverse 
events that cause withdrawal will be tabulated.  All adverse events will be listed.
All clinical laboratory data will be displayed in listings grouped by type of laboratory test 
(eg, hematology, blood chemistry) for each sample collection date.  Values outside of the 
normal range will be noted; the respective normal high or low value will be presented in 
parentheses, linked to the abnormal laboratory value.  Laboratory values will be summarized 
as median changes from baseline and also by frequency of occurrence of clinically 
significant abnormal values.
All vital sign measurements will be displayed in listings by subject for each sample 
collection date and time.
Centrally over read ECG variables will be summarized by mean change from baseline to 
each measurement time for heart rate, PR interval, RR interval, QRS width, QT interval and 
QTcB (Bazett’s correction) and QTcF (Fridericia’s correction) values.  Additionally, the 
incidence of categorical increases in QTc intervals will be provided.  Categories for QTcF 
and QTcB are 450 msec, 480 msec, and 500 msec.  Categories for QTcF and QTcB as 
change from baseline are 30 msec increase, 60 msec increase and 75 msec increase.  
QTcF is considered the primary QTc value as this correction is more appropriate.
9.4. Interim Analysis
No formal interim analysis will be conducted for this study.  However, as this is an 
open-label study, the sponsor may conduct unblinded reviews of the data during the course of 
the study for the purpose of safety assessment, facilitating dose-escalation decisions, 
facilitating pharmacokinetic (PK)/pharmacodynamics (PD) modeling, and/or to support 
clinical development. 
9.5. Data Monitoring Committee 
This study will utilize an External Data Monitoring Committee (E-DMC).  The E-DMC will 
be responsible for ongoing monitoring of the safety of subjects in the study according to the 
Charter.  The recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for final decision.  Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of endpoint events and of safety data which are not 
endpoints, to regulatory authorities, as appropriate.  The E-DMC membership has been 


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restricted to individuals free of apparent significant conflicts of interest.  The source of such 
conflicts may be financial, scientific, or regulatory in nature.  Thus, neither study 
investigators nor individuals employed by the sponsor regulatory agencies are to be members 
of the E-DMC.  Membership is to be for the duration of the clinical trial including the post 
study generation of final reports.  The E-DMC will meet on a regular basis and will operate 
independently of the sponsor. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the institutional review boards /ethics committees (IRB/EC), and/or to quality 
assurance audits performed by Pfizer, or companies working with or on behalf of Pfizer, 
and/or to inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
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 


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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 are true. Any corrections to entries made in the CRFs or 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 or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
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 and hospital records), all original signed 
informed consent and assent 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, 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 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.


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12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent and assent documents, and other relevant 
documents, eg, recruitment advertisements, if applicable, from the IRB/EC.  All 
correspondence with the IRB/EC should be retained in the investigator file.  Copies of 
IRB/EC approvals should be forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
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. 
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 staffs 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.


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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.
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 
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.
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. 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 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that 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.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as last subject last visit (LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product 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, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within a time period set by Pfizer.  No longer than 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.


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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.
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 supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  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, the investigator is free to publish separately, subject to the other 
requirements of this section.


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For all publications relating to the study, the 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 CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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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 2016.
11.
Poznanski EO, Freemen LN, & Mokros HB. (1985). Children’s Depression Rating 
Scale-Revised. Psychopharmacol Bull, 21, 979-989.
12.
Poznanski EO & Mokros HB. (1996). Children’s Depression Rating Scale, Revised, 
Manual. LA: Western Psychological Services.
13.
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand, 1970;212:11-19.


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14.
Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154: 
672-676.
15.
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand, 1970;212:11-19.
16.
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.
17.
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.
18.
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.
19.
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.
20.
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.
21.
Shaffer D, Gould MS, Brasic J, et al. A Children's Global Assessment Scale (CGAS). 
Arch Gen Psychiatr. 1983; 40(11):1228 31.


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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
AST
aspartate aminotransferase
BAS
Barnes Akathisia Rating Scale
BID
Twice daily
BBS
Biospecimen Banking System
BMI
Body Mass Index
BMS
BioMedical Systems
BUN
blood urea nitrogen
C-CASA
Columbia Classification Algorithm of Suicide Assessment 
CDC
Child Development Chart
CDRS-R
Child Depression Rating Scale – Revised
CGAS
Children’s Global Assessment Scale
CGI-S
Clinical Global Impression of Severity
CK
creatine kinase
CNS
Central nervous system
CRF
case report form
CRO
contract research organization
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CT
Clinical Trial
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A4
Cytochrome P450 3A4
DB
Double Blind
DHEA
dehydroepiandrosterone
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DSM
Diagnostic and Statistical Manual of Mental Disorders
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCRF
Electronic Case Report Form
E-DMC
external data monitoring committee 


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Abbreviation
Term
EDP
exposure during pregnancy
EU
European Union
EudraCT
European Clinical Trials Database
ET
Early Termination
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
HbA1c
glycosylated hemoglobin
HR
Heart rate
HRQL
health-related quality of life
5-HT1A
5-Hydroxytryptamine Receptor 1A
5-HT2A
5-Hydroxytryptamine Receptor 2A
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
ID
identification
IM
Intramuscular
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IWR
interactive Web-based response
K2EDTA
dipotassium ethylenediaminetetraacetic acid
K-SADS
Kiddie Schedule for Affective Disorders and Schizophrenia
LDL
Low-density lipoprotein
LDH
Lactate dehydrogenase
LFT
liver function test
LSLV
last subject last visit 
MnB
meningitidis serogroup B
MAO
mono amine oxidase
N or n
number
N/A
not applicable
NSAIDs
non-steroidal antiinflammatory drugs
OL
open label
PCD
primary completion date
PD
Pharmacodynamics
PFS
prefilled syringe


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Final Protocol Amendment 1, 19 February 2019 
PFIZER CONFIDENTIAL
Page 75
Abbreviation
Term
PGx
Pharmacogenomics(s)
PI
principal investigator
PK
pharmacokinetic
PP
Per Protocol
PR
Pulse rate 
PREA
Pediatric Research Equity Act
PRN
when necessary
PSRAE
Possibly Suicide Related Adverse Events
PT
prothrombin time
QTcB
Bazett's correction
QTc
QT corrected
QTcF
Fridericia's correction
RCTs
randomized clinical trials
RNA
ribonucleic acid
RR
respiration rate
SAE
serious adverse event
SAP
statistical analysis plan
SARS
Simpson Angus Rating Scale
SC
subcutaneous
SGOT -
serum glutamic oxaloacetic transaminase
SGPT -
serum glutamic pyruvic transaminase
s-NDA
Supplemental New Drug Application
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TSH
thyroid-stimulating hormone
UDS
urine Drug Screen
ULN
upper limit of normal
US
United States
YMRS
Young Mania Rating Scale


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Final Protocol Amendment 1, 19 February 2019 
PFIZER CONFIDENTIAL
Page 76
Appendix 2. Criteria for Training Approval without Sponsor Review 
Rating Scale
Educational Level*
Prior Clinical and 
Pediatric Experience
Prior Scale Experience
C-SSRS
MD or DO; PhD in 
Clinical or Counseling 
Psychology; RN or 
Master’s level degree in 
a medical, social work, 
or mental health field
1 year clinical 
experience with pediatric 
population and/or 
pediatric clinical trial 
experience
Prior training with C-SSRS 
within the past two years with 
valid documented certification 
will exempt rater from having 
to retake C-SSRS training
YMRS
Child and Adolescent 
Psychiatrist (or in the 
case of countries 
outside the US, the 
local country equivalent 
in education and 
training) or
Adult Psychiatrist (PI
or SubI) or Doctoral
Level Psychologist
1 year clinical 
experience with pediatric 
population and/or 
pediatric clinical trial 
experience
5 administrations of any 
clinician rated interview based 
scale such as CGAS, CDRS-R, 
MADRS, HAM-D
MD, MA, MS, MSW, 
RN, BS, BA
1 year clinical 
experience with pediatric 
population and/or 
pediatric clinical trial 
experience
5 administrations of any 
clinician rated interview based 
scale
CGI
Child and Adolescent 
or Psychiatrist (or in the 
case of countries 
outside the US, the 
local country equivalent
in education and 
training) or Adult 
Psychiatrist, (PI or 
SubI) or Doctoral Level 
Psychologist
1 year clinical 
experience with pediatric 
population and/or 
pediatric clinical trial 
experience
5 administrations of the CGI or 
similar type global rating scale 
such as CGIC
CDRS-R/CGAS
Child and Adolescent 
or Psychiatrist (or in the 
case of countries 
outside the US, the 
local country equivalent
in education and 
training) or Adult 
Psychiatrist; or 
Doctoral Level 
Psychologist
1 year clinical
experience with pediatric 
population and/or 
pediatric clinical trial 
experience
5 administrations of any 
clinician rated interview based 
scale such as YMRS, HAM-D, 
MADRS, CDRS-R or CGAS
MD, MA, MS, MSW, 
RN, BS, BA
1 year clinical 
experience with pediatric 
population and/or 
pediatric clinical trial 
experience
5 administrations of any 
clinician rated interview based 
scale
K-SADS
Child and, Adolescent 
Psychiatrist (or in the 
1 year clinical 
experience with pediatric 
5 administrations of any 
diagnostic interview based 


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Final Protocol Amendment 1, 19 February 2019 
PFIZER CONFIDENTIAL
Page 77
Rating Scale
Educational Level*
Prior Clinical and 
Pediatric Experience
Prior Scale Experience
case of countries 
outside the US, the 
local country equivalent 
in education and 
training) or Adult 
Psychiatrist (PI or SubI) 
or Doctoral Level 
Psychologist
population and/or 
pediatric clinical trial 
experience
scale such as SCID, MINI, 
MINI-KID, DIS, CIDI
AIMS/BARS/SAS
Child and Adolescent 
Psychiatrist (or in the 
case of countries 
outside the US, the 
local country equivalent 
in education and 
training) or Adult 
Psychiatrist or other 
physician
1 year clinical 
experience with pediatric 
population and/or 
pediatric clinical trial 
experience
5 administrations of any 
movement scale such as 
AIMS/BARS/SAS or ESRS-A, 
UPDRS or the Global Dystonia 
Scale
* International equivalencies will be accepted.  Doctoral level psychologist (PhD or PsyD) must be trained in 
child development.
** Upon 2 year expiration of documented certification, raters will be required either to retake C-SSRS training 
or resubmit valid, current documented certification.  Should the two years lapse during the course of the study, 
retraining updated training and a renewed certificate will be required.

SAP_001.pdf: 
Protocol A1281201 Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol A1281201
A 26-WEEK OPEN-LABEL EXTENSION STUDY EVALUATING THE SAFETY 
AND TOLERABILITY OF FLEXIBLE DOSES OF ORAL ZIPRASIDONE IN 
CHILDREN AND ADOLESCENTS WITH BIPOLAR I DISORDER (MOST 
RECENT EPISODE MANIC)
Statistical Analysis Plan 
(SAP)
Version:
1.1 (Amendment)
Author:
 
Date:
2-MAY-2019
PPD


Protocol A1281201 Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
1. AMENDMENTS FROM PREVIOUS VERSIONS..............................................................3
2. INTRODUCTION .................................................................................................................3
2.1. Study Design .............................................................................................................3
2.2. Study objective..........................................................................................................5
2.3. Allocation to Treatment ............................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES AND CONVENTIONS.............................5
3.1. Efficacy Endpoints ....................................................................................................5
3.2. Special Safety Endpoints...........................................................................................5
3.3. Safety Endpoints .......................................................................................................5
3.4. Baseline Variables.....................................................................................................6
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................6
4.1. Safety Analysis Set....................................................................................................6
4.2. Treatment Misallocations..........................................................................................7
4.3. Protocol Deviations/Violations .................................................................................7
5. GENERAL METHODOLOGY AND CONVENTIONS......................................................7
5.1. Hypotheses and Decision Rules ................................................................................7
5.2. General Methods .......................................................................................................7
5.3. Methods to Manage Missing Data ............................................................................7
6. ANALYSES AND SUMMARIES ........................................................................................7
6.1. Disposition of subjects and Withdrawals..................................................................7
6.2. Baseline Summaries ..................................................................................................7
6.3. Efficacy Analyses......................................................................................................8
6.4. Special Safety Analyses ............................................................................................8
6.5. Safety Analyses.........................................................................................................8
6.5.1. Adverse Events.............................................................................................8
6.5.2. Laboratory Data............................................................................................9
6.5.3. Physical Exam ..............................................................................................9
6.5.4. Body Weight and Height, BMI, Waist Circumference.................................9
6.5.5. Vital Signs ....................................................................................................9
6.5.6. Electrocardiograms.......................................................................................9
6.6. Subgroup analysis ...................................................................................................10
7. INTERIM ANALYSES.......................................................................................................10


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1. AMENDMENTS FROM PREVIOUS VERSIONS 

Added subgroup analysis section.
2. INTRODUCTION
Note: In this document any text taken directly from the protocol (A121201 protocol 
amendment 1 dated 19February2019) is italicized.
This protocol describes a 6-month, open label extension study (A1281201) of the 
A1281198 study.  The purpose of adding this extension study to the ongoing Geodon 
pediatric bipolar program is to obtain additional longer term safety data in children and 
adolescents with Bipolar I disorder treated with ziprasidone. 
Studies A1281198 and A1281201 are being conducted to fulfill 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 10 to 17 years of age, which was issued 
by the United States (US) Food and Drug Administration (FDA) to Pfizer in August 2004. 
Ziprasidone is an atypical antipsychotic with a high affinity for the dopamine D2 receptor 
and the 5-Hydroxytryptamine Receptor 2A (5-HT2A) receptors.  It blocks re-uptake of 
serotonin and norepinephrine and exhibits 5-Hydroxytryptamine Receptor 1A (5-HT1A)
agonist activity.  The indication for this study is pediatric Bipolar I Disorder.  The study will 
include out-patient and/or inpatient, male and female subjects aged 10-17 (inclusive) who 
meet the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM V) 
diagnostic criteria for Bipolar I Disorder (current or most recent episode manic) and who 
participated in Study A1281198.
2.1. Study Design
This 26 week open label extension study is designed to provide information on the safety and 
tolerability of oral ziprasidone (20 to 80 mg BID with meals) during long term 
administration in children and adolescents with Bipolar I Disorder (current or most recent 
episode manic).  It will enroll subjects who have participated in the 4 week, double blind, 
placebo controlled safety and efficacy trial, Study A1281198, meet study entry criteria, and 
wish to receive treatment with open label ziprasidone.
The number of subjects entering this open-label trial will be determined by the number of 
subjects electing to continue treatment after completing or withdrawing from the preceding 
double blind Study A1281198.  We estimate that approximately 55 subjects randomized in the 
double blind study (based on the increased sample size of N=194 subjects) will be eligible to 
continue in this open label extension.  With an expected dropout rate of approximately 35%, 
this gives an estimate of approximately 40 subjects to complete this 26 week open label study 
(if all 55 subjects enter the extension study).


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The final visit of the double blind trial (Week 4 or early termination visit from A1281198) 
will serve as the Baseline Visit for the extension study. The first 1-14 days of 
Study A1281201 will be considered a transition period during which the study drug will 
continue to be administered under double-blind conditions.  During this double-blind 
transition period, subjects who were on placebo in Study A1281198 will be provided active 
medication that will allow them to be titrated up to the appropriate weight-adjusted target 
dose, following titration schedule that was employed in Study A1281198.  Subjects who were 
on active medication (ziprasidone) at the end of Study A1281198 will continue on that 
treatment course under double-blind conditions.  At the end of the double-blind transition 
period, all subjects will receive open label ziprasidone.
Any subject who cannot tolerate the transition study medication during Week 1 should be 
discontinued from the study.
After the Week 2 visit for the > 45 kg subjects and after the Week 1 visit for the <45 kg 
subjects, dosing will be open label and flexible, with dosing adjustments made at the 
discretion of the investigator to maintain optimal efficacy and tolerability.  For subjects with 
a body weight of >45 kg, the target dose range is a total daily dose of 120-160 mg/day given 
in two divided doses with food.  For subjects with a body weight <45 kg, the target dose 
range is a total daily dose of 60-80 mg/day given in two divided doses with food. 
Subjects who cannot tolerate a dose of 80 mg/day will be allowed to have a dose reduction 
and to continue study treatment at a lower dose that is tolerable to them.  The minimum 
permitted dose is 40 mg/day (20 mg BID) for all subjects.
Post Baseline visits will occur at Weeks 1, 2, 4, 6, 10, 14, 18, 22 and 26 during treatment, 
with a follow up visit at Week 27.


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2.2. Study objective
To assess the safety and tolerability of oral ziprasidone (20-80 mg BID) during long term, 
open label administration in children and adolescents with Bipolar I Disorder who 
participated in Study A1281198.
2.3. Allocation to Treatment
Throughout most of this study, ziprasidone will be administered as open label (OL) 
investigational product to all subjects. However, the dose transition from the double-blind 
study drug administered in Study A1281198 to the open-label dosing in the extension trial 
A1281201 will be conducted under double-blind conditions.
The double-blind dose transition phase of Study A1281201 will comprise Weeks 1 and 2 for 
subjects ≥45 kg and Week 1 for subjects <45 kg.  The double-blind (DB) medication for this 
transition period will be assigned according to the subject’s randomization number in the 
preceding study so that the investigator remains blinded during this period. 
At the baseline visit of the A1281201 study, subjects will transition onto active medication if 
previously assigned to the placebo group or continue on active study drug.  Over the course 
of the double-blind dose transition period, subjects <45 kg will be transitioned to a total 
daily dose of 60 mg a day by Day 7 of Week 1 and subjects ≥45 kg will be transitioned to a 
total daily dose of 120 mg a day by Day 10 of Week 2.  All medication will remain blinded 
until the end of the transition period.  
3. ENDPOINTS AND BASELINE VARIABLES AND CONVENTIONS
For collection schedules for all endpoints, please refer to the protocol.
3.1. Efficacy Endpoints

Young Mania Rating Scale (YMRS).

Clinical Global Impression of Severity (CGI-S).

Children’s Global Assessment Scale (CGAS).
3.2. Special Safety Endpoints

Child Depression Rating Scale - Revised (CDRS-R).

Columbia Suicide Severity Rating Scale (C-SSRS).

Movement Disorder Scales (SARS, BAS, and AIMS).
3.3. Safety Endpoints

Adverse event reporting;

Clinical laboratory testing;


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
Physical examinations;

Blood pressure and pulse;

Height and weight;

Body Mass Index (BMI) and BMI Z score;

Waist circumference;
Electrocardiograms, including QTc.
3.4. Baseline Variables
No baseline covariates in the planned analysis.
Baseline visit for the open-label extension study will be the final visit of the double blind trial 
(Week 4 or early termination visit from A1281198), except for safety ECG parameters. For 
ECG parameters, baseline values will be the value from the Baseline visit in the double-blind
study A1281198.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
4.1. Safety Analysis Set
As the objective of the study is long-term safety and tolerability of ziprasidone, only one
analysis set, “Safety Analysis Set”  defined below will be used for data summaries.
The Safety Analysis Set (SAS) will include all subjects who took at least one dose of study
medication in this open-label extension study.
All summaries will be based on the “as reported” visits (as recorded on the Case Report 
Forms).
For data summary purposes, subjects will be classified into one of the following two groups:

Ziprasidone/Ziprasidone: randomized to ziprasidone in the preceding double-blind
study (and on ziprasidone in the current open-label extension study).

Placebo/Ziprasidone: randomized to placebo in the preceding double-blind study (and
on ziprasidone in the current open-label extension study).
In addition, the above two groups will be combined as:

Combined: combination of the two groups Ziprasidone/Ziprasidone and
Placebo/Ziprasidone. This is essentially the set of all subjects in the current
open-label extension study.
Data summaries will be done based on Ziprasidone/Ziprasidone and Placebo/Ziprasidone, as
well as Combined.


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4.2. Treatment Misallocations
If a subject took incorrect treatment in the preceding double blind study, then the subject will 
be reported under the treatment they actually received. For example, if a subject randomized 
to placebo but took Ziprasidone instead in the preceding double-blind study, then the subject 
will be reported under “Ziprasidone/Ziprasidone” rather then “Placebo/Ziprasidone”. 
4.3. Protocol Deviations/Violations
A full list of clinically important protocol deviations/violations will be included in the 
Clinical Study Report. Note that protocol deviations/violations will not exclude subjects 
from the “Safety Analysis Set” defined in Section 5.1.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
As this is an open-label study with no comparator, no formal statistical hypothesis testing will
be conducted.
5.2. General Methods
As this is an open label study with no comparator, no inferential statistics will be performed.  
Quantitative variables will be described by standard descriptive statistics (n, mean, standard 
deviation, minimum, and maximum, 95% confidence intervals), and qualitative variables will 
be summarized by frequency tables.  Summaries will include data for all subjects who took at 
least one dose of investigational product in this open label extension study.
5.3. Methods to Manage Missing Data
For any efficacy or special assessment rating scale/subscale or special safety variables where 
there is a missing rating (item), that scale or subscale will be scored as missing. If the whole 
scale has a missing item but the subscale has no items missing, the total score for the scale 
will be scored as missing but the subscale score will be computed.
6. ANALYSES AND SUMMARIES
All analyses will be conducted within the SAS population. Analyses will be descriptive in 
nature. No formal interim analyses are planned.  
6.1. Disposition of subjects and Withdrawals
The numbers and percentage of subjects randomized, completing, and withdrawing, along 
with reasons for withdrawal, will be tabulated, overall and by treatment group.  
6.2. Baseline Summaries
All demographic, baseline characteristics and pre-treatment conditions will be summarized 
using the safety population.  Descriptive statistics, including number of patients, mean, 
standard error, median, and range for continuous variables, and frequency and percent for 
categorical variables, will be provided for all demographic, baseline characteristics, and 
pre-treatment conditions.  


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PFIZER CONFIDENTIAL 
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6.3. Efficacy Analyses
No formal efficacy or outcomes analyses will be performed for this study.  However data on 
the YMRS, CGI-S and CGAS will be summarized using descriptive statistics as described 
above.
6.4. Special Safety Analyses
No formal analyses for special safety assessments will be performed for this study.  However 
data on the C-SSRS, CDRS-R and Movement disorder scales (SARS, BAS, AIMS) will be 
summarized using descriptive statistics as described above.
6.5. Safety Analyses
No formal statistical analysis will be conducted on any of the below safety data.
The safety assessments include:

Adverse event reporting;

Clinical laboratory testing;

Physical examinations;

Blood pressure and pulse;

Height and weight;

Body Mass Index (BMI) and BMI Z score;

Waist circumference;

Electrocardiograms, including QTc.
6.5.1. Adverse Events
All randomized subjects who receive at least one dose of antipsychotic treatment will be 
included in the safety data summarization.  All treatment emergent adverse events that are 
observed from the time of first dosing with open label investigational product until the end of 
study participation will be included in data summaries. All causality discontinuations and 
treatment emergent discontinuations from the study will be summarized.
An adverse event is considered treatment emergent relative to a given treatment if:

the event occurs for the first time during the time of first dosing with open label 
investigational product until the end of study participation and was not seen prior to 
the start of treatment in open-label extension (for example, during the baseline or 
double-blind study), or


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
the event was seen prior to the start of treatment but increased in severity during 
treatment.
All adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities.  The incidence of treatment emergent adverse events will be tabulated by system 
organ class.  The incidence of treatment emergent adverse events will be displayed by 
severity and attribution.  In addition, the incidence of serious adverse events and adverse 
events that cause withdrawal will be tabulated.  All adverse events will be listed.
6.5.2. Laboratory Data
All clinical laboratory data will be displayed in listings grouped by type of laboratory test 
(eg, hematology, blood chemistry) for each sample collection date.  Values outside of the 
normal range will be noted; the respective normal high or low value will be presented in 
parentheses, linked to the abnormal laboratory value.  Laboratory values will be summarized 
as median changes from baseline and also by frequency of occurrence of clinically 
significant abnormal values.
6.5.3. Physical Exam
Physical examinations are to be performed at the Baseline visit (last visit in Study A1281198) 
and at Week 26 (or early termination).  Any significant physical examination finding should 
be recorded as an adverse event.
6.5.4. Body Weight and Height, BMI, Waist Circumference
Data for height, weight, BMI, and waist circumference will be summarized by time point 
using descriptive statistics.  Additionally, height, weight, and BMI will be standardized using 
CDC (Child Development Chart) 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.
6.5.5. Vital Signs
All vital sign measurements will be displayed in listings by subject for each sample collection 
date and time.
6.5.6. Electrocardiograms
Centrally over read ECG variables will be summarized by mean change from baseline to 
each measurement time for heart rate, PR interval, RR interval, QRS width, QT interval and 
QTcB (Bazett’s correction) and QTcF (Fridericia’s correction) values.  Additionally, the 
incidence of categorical increases in QTc intervals will be provided.  Categories for QTcF 
and QTcB are ≥450 msec, ≥480 msec, and ≥500 msec.  Categories for QTcF and QTcB as 
change from baseline are ≥30 msec increase, ≥60 msec increase and ≥75 msec increase.  
QTcF is considered the primary QTc value as this correction is more appropriate.


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6.6. Subgroup analysis
A subgroup analysis of subjects enrolled in Chinese sites will be conducted on the primary, 
secondary efficacy endpoints, as well as all safety endpoints.  The Sponsor plans to utilize 
the subgroup analysis from both completed pediatric Studies A1281198 and open label study 
A1281201, to support a submission seeking the indication of the pediatric bipolar disorder 
for Zeldox in China.
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study.  However, as this is an 
open-label study, the sponsor may conduct unblinded reviews of the data during the course 
of the study for the purpose of safety assessment, facilitating dose-escalation decisions, 
facilitating pharmacokinetic (PK)/pharmacodynamics (PD) modeling, and/or to support 
clinical development.