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Clinical Trial Results:
26-week open-label extension study evaluating the safety and tolerability of flexible doses of oral ziprasidone in adolescent subjects with schizophrenia.

Summary
EudraCT number	2005-005502-23
Trial protocol	SE DE
Global end of trial date	16 Apr 2009

Results information
Results version number	v1
This version publication date	11 May 2016
First version publication date	23 Jul 2015
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

A1281135

ISRCTN number

US NCT number

NCT00265382

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 00 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 00 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

30 Nov 2011

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Apr 2009

Was the trial ended prematurely?

Yes

Main objective of the trial

To assess the safety and tolerability of oral ziprasidone (40-80 milligram [mg] twice a day [BID]) during long-term, open-label administration in adolescent subjects with schizophrenia.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Jun 2006

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Singapore: 2

Country: Number of subjects enrolled

United States: 44

Country: Number of subjects enrolled

India: 28

Country: Number of subjects enrolled

Russian Federation: 66

Country: Number of subjects enrolled

Malaysia: 14

Country: Number of subjects enrolled

Peru: 8

Country: Number of subjects enrolled

Costa Rica: 3

Country: Number of subjects enrolled

Ukraine: 48

Country: Number of subjects enrolled

Colombia: 8

Worldwide total number of subjects

221

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

221

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study enrolled adolescent subjects with schizophrenia, ages 13-17 years, who participated in the double-blind placebo controlled Study A1281134 (Eudract Number: 2005-005502-23) (NCT00257192) who met qualification criteria and wished to receive treatment with open-label ziprasidone.

Screening details

The study was conducted at 60 centers in 9 countries between 15 June 2006 to 16 April 2009.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Ziprasidone

Arm description

Ziprasidone capsules administered BID with meals.

Arm type

Experimental

Investigational medicinal product name

Ziprasidone

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Titrated over a 2-week period, starting with an evening dose of 20 mg/day, and subsequent dose increases of 20 mg/day every second day up to a target dose of 80 to 160 mg/day for subjects weighing >=45 kilograms (kg). For subjects with a body weight <45 kg, the maximum permitted dose was 80 mg/day (40 mg BID). Doses could have been reduced to a minimum of 40 mg/day (20 mg BID).

Number of subjects in period 1	Ziprasidone
Started	221
Completed	76
Not completed	145
Consent withdrawn by subject	13
Adverse Event	21
Death	1
Miscellaneous	6
Study terminated by sponsor	94
Lost to follow-up	3
Laboratory Abnormality	1
Lack of efficacy	6

Baseline characteristics

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Reporting group title

Ziprasidone

Reporting group description

Ziprasidone capsules administered BID with meals.

Reporting group values	Ziprasidone	Total
Number of subjects	221	221
Age categorical
Baseline data are from the preceding Study A1281134 (Eudract Number: 2005-005502-23) (NCT00265382).
Units: Subjects
>12 years and <13 years at start of treatment	3	3
13 to 17 years	218	218
Gender categorical
Units: Subjects
Female	90	90
Male	131	131

End points

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Reporting group title

Ziprasidone

Reporting group description

Ziprasidone capsules administered BID with meals.

Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[1]

End point description

All observed or volunteered treatment-emergent AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported. Safety Analysis Set = all subjects who took at least one dose of study medication. In this table, the number of subjects with AEs is based on a 0 percent (%) AE threshold whereas the number of subjects with AEs reported in the AE section are based on a 5% AE threshold.

End point type

Primary

End point timeframe

26 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this outcome measure.

End point values	Ziprasidone
Number of subjects analysed	221
Units: subjects
AEs	137
SAEs	16

No statistical analyses for this end point

Secondary: Number of Subjects With Change From Baseline to Each Pubertal Stage of Development as Assessed by the Tanner Adolescent Pubertal Self Assessment

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End point title

Number of Subjects With Change From Baseline to Each Pubertal Stage of Development as Assessed by the Tanner Adolescent Pubertal Self Assessment

End point description

Tanner Adolescent Pubertal Staging Questionnaire: used to document the stage of development of secondary sexual characteristics. Female pubertal development staged by pubic hair development and breast size; males pubertal development staged by size of the genitalia and development of pubic hair. Rated in 5 stages: stage 1 (no development) to 5 (adult-like development in quantity and size). Safety Analysis Set. Baseline data from Study A1281134 (Eudract Number: 2005-005502-23) (NCT00257192) served as the baseline for A1281135.

End point type

Secondary

End point timeframe

Baseline, Week 26, Early Termination (ET)

End point values	Ziprasidone
Number of subjects analysed	73 ^[2]
Units: subjects
Pubic Hair, Week 26 (Stage 1)	1
Pubic Hair, Week 26 (Stage 2)	1
Pubic Hair, Week 26 (Stage 3)	11
Pubic Hair, Week 26 (Stage 4)	39
Pubic Hair, Week 26 (Stage 5)	21
Pubic Hair, ET (Stage 1)	0
Pubic Hair, ET (Stage 2)	10
Pubic Hair, ET (Stage 3)	22
Pubic Hair, ET (Stage 4)	59
Pubic Hair, ET (Stage 5)	30

Notes
[2] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Change From Baseline in Children's Problem Behavior and Aggression Questionnaire (CPBAQ) Total Score

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End point title

Change From Baseline in Children's Problem Behavior and Aggression Questionnaire (CPBAQ) Total Score

End point description

CPBAQ: 19-item parent or legal guardian completed questionnaire to rate the child's verbal (such as yelling or cursing) and physical aggression (such a fighting with peers or being cruel to an animal) during the past week. Behavior was rated on a 4-point scale; range 0 (behavior did not occur or was not a problem) to 3 (behavior occurred a lot or was severe problem). Total score range 0 to 57; higher scores indicate a greater frequency and severity of aggression. Safety Analysis Set. n=number of subjects with analyzable data at post-baseline observation. Baseline was the last available observation from Study A1281134 (EudraCT Number: 2005-005502-23) (NCT00257192). Last Observation Carried Forward (LOCF) imputation used for Week 26 LOCF time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 6, 18, 26, ET

End point values	Ziprasidone
Number of subjects analysed	208 ^[3]
Units: scores on a scale
arithmetic mean (standard deviation)
Week 2 (n=178)	-0.3 ± 4.8
Week 6 (n=153)	-0.8 ± 6.1
Week 18 (n=93)	-0.5 ± 6.5
Week 26 (n=68)	0.7 ± 7.7
ET (n=113)	0.5 ± 7.1
Week 26 LOCF (n=177)	-0.5 ± 7

Notes
[3] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Change From Baseline in Child Depression Rating Scale - Revised (CDRS-R): Total Score

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End point title

Change From Baseline in Child Depression Rating Scale - Revised (CDRS-R): Total Score

End point description

CDRS-R: clinician-rated interview-based scale (with both child and parent or guardian) to assess 17 distinct symptom areas to derive an index of depression severity. Discrepancies between informants' responses were resolved by using most impaired rating given by valid informant. Rated on a 7-point scale; range from 1 (no impairment) to 7 (indicates greater impairment). Total score calculated as sum of the 17 items (range 1 to 119); higher score indicates greater impairment. Safety Analysis Set. n=number of subjects with analyzable data at post-baseline observation. Baseline was the last available observation from Study A1281134 (EudraCT Number: 2005-005502-23) (NCT00257192). LOCF imputation used for Week 26 LOCF time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 6, 10, 14, 18, 22, 26, ET

End point values	Ziprasidone
Number of subjects analysed	214 ^[4]
Units: scores on a scale
arithmetic mean (standard deviation)
Week 1 (n=198)	-1.4 ± 4.8
Week 2 (n=188)	-2.2 ± 6.1
Week 6 (n=160)	-3.5 ± 6.3
Week 10 (n=129)	-4.6 ± 7.3
Week 14 (n=105)	-5 ± 7.4
Week 18 (n=94)	-4.9 ± 8.1
Week 22 (n=78)	-5.1 ± 7.9
Week 26 (n=72)	-5.3 ± 7.8
ET (n=122)	-2.7 ± 7.3
Week 26 LOCF (n=197)	-4.5 ± 7

Notes
[4] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Change From Baseline in Central Nervous System (CNS) Vital Signs Cognitive Test Battery (Includes Sedation Item): Subscales

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End point title

Change From Baseline in Central Nervous System (CNS) Vital Signs Cognitive Test Battery (Includes Sedation Item): Subscales

End point description

Computerized subject-administered test battery with subtests for verbal and visual memory, processing speed, nonverbal reasoning, executive functioning, working memory, sustained attention. Computerized 7- point sedation item (0 [not sleepy] to 10 [very sleepy]) was completed prior to test battery. Neurocognitive index score was derived from subtest scores per an algorithm. Index score and subtest scores assessed the subject's changes in cognition. Scores were rated as above average (score >109), average (90 to 109), below average (80 to 89), or well below average (70 to 79). Safety Analysis Set. n=number of subjects with analyzable data at post-baseline observation. Baseline was the last available observation from Study A1281134 (EudraCT Number: 2005-005502-23) (NCT00257192). LOCF imputation used for Week 26 LOCF time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 6 and 26, ET

End point values	Ziprasidone
Number of subjects analysed	212 ^[5]
Units: scores on a scale
arithmetic mean (standard deviation)
Sedation: Week 6 (n=149)	0.1 ± 1.7
Sedation: Week 26 (n=70)	-0.2 ± 1.5
Sedation: ET (n=102)	-0.1 ± 2
Sedation: Week 26 LOCF (n=153)	-0.2 ± 1.7
Verbal Memory: Week 6 (n=150)	-1.3 ± 13.7
Verbal Memory: Week 26 (n=71)	0.6 ± 14
Verbal Memory: ET (n=103)	-0.7 ± 14.6
Verbal Memory: Week 26 LOCF (n=155)	0.3 ± 14.5
Visual Memory: Week 6 (n=148)	-3.6 ± 13.7
Visual Memory: Week 26 (n=71)	-2.1 ± 15.5
Visual Memory: ET (n=103)	-1.9 ± 12.7
Visual Memory: Week 26 LOCF (n=154)	-1.5 ± 14.4
Processing Speed: Week 6 (n=148)	-1.2 ± 11.4
Processing Speed: Week 26 (n=71)	2.1 ± 10.2
Processing Speed: ET (n=103)	-1.4 ± 19
Processing Speed: Week 26 LOCF (n=153)	0.5 ± 12
Reasoning: Week 6 (n=145)	-0.3 ± 14.1
Reasoning: Week 26 (n=71)	3 ± 11.3
Reasoning: ET (n=100)	1.9 ± 14.9
Reasoning: Week 26 LOCF (n=151)	1.5 ± 14.3
Executive Functioning: Week 6 (n=145)	2 ± 16.7
Executive Functioning: Week 26 (n=71)	2 ± 16.8
Executive Functioning: ET (n=100)	2.4 ± 15.7
Executive Functioning: Week 26 LOCF (n=151)	2.4 ± 16.9
Working Memory: Week 6 (n=145)	-0.5 ± 12.6
Working Memory: Week 26 (n=68)	0.8 ± 16.4
Working Memory: ET (n=99)	0.3 ± 12.1
Working Memory: Week 26 LOCF (n=150)	0.7 ± 14.2
Sustained Attention: Week 6 (n=145)	0.2 ± 12
Sustained Attention: Week 26 (n=68)	1.9 ± 14
Sustained Attention: ET (n=99)	-0.6 ± 12.2
Sustained Attention: Week 26 LOCF (n=150)	1.2 ± 12.7

Notes
[5] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Change From Baseline in CNS Vital Signs Cognitive Test Battery: Neurocognitive Index

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End point title

Change From Baseline in CNS Vital Signs Cognitive Test Battery: Neurocognitive Index

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 6 and 26, ET

End point values	Ziprasidone
Number of subjects analysed	208 ^[6]
Units: scores on a scale
arithmetic mean (standard deviation)
Neurocognitive Index: Week 6 (n=144)	-0.6 ± 7.2
Neurocognitive Index: Week 26 (n=68)	1.3 ± 7.3
Neurocognitive Index: ET (n=99)	0.5 ± 6.3
Neurocognitive Index: Week 26 LOCF (n=150)	0.7 ± 7.7

Notes
[6] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Change From Baseline in Simpson-Angus Rating Scale (SARS)

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End point title

Change From Baseline in Simpson-Angus Rating Scale (SARS)

End point description

SARS: 10-item clinician rated instrument to assess parkinsonian symptoms (7 items) and related extrapyramidal side effects (3 items): gait, arm dropping, shoulder shaking, elbow rigidity, leg pendulousness, glabellar tap, tremor, and salivation. Head dropping (modified SARS item 7) substituted for head rotation. Anchored 5-point scale: range 0 (absence of condition, normal) to 4 (most extreme form of condition). Total score is sum of individual item scores (range 0 to 40); higher score indicates more affected. Safety Analysis Set. n=number of subjects with analyzable data at post-baseline observation. Baseline was the last available observation from Study A1281134 (EudraCT Number: 2005-005502-23) (NCT00257192). LOCF imputation used for Week 26 LOCF time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 6, 10, 14, 18, 22, 26, ET

End point values	Ziprasidone
Number of subjects analysed	221 ^[7]
Units: scores on a scale
arithmetic mean (standard deviation)
Week 1 (n=206)	-0.05 ± 1.4
Week 2 (n=197)	-0.11 ± 1.3
Week 6 (n=168)	-0.04 ± 1.7
Week 10 (n=135)	-0.1 ± 1.6
Week 14 (n=110)	-0.02 ± 1.9
Week 18 (n=99)	0.02 ± 1.4
Week 22 (n=82)	-0.04 ± 1.7
Week 26 (n=76)	-0.32 ± 1.4
ET (n=127)	-0.31 ± 2
Week 26 LOCF (n=206)	-0.15 ± 1.5

Notes
[7] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Change From Baseline in Barnes Akathisia Rating Scale (BAS) Global Clinical Assessment Item

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End point title

Change From Baseline in Barnes Akathisia Rating Scale (BAS) Global Clinical Assessment Item

End point description

BAS: clinician rated scale to assess akathisia to determine the degree of subjective restlessness and distress associated with restlessness. First 3 items (Objective, Subjective, and Distress related to restlessness) rated on a 4-point scale with range 0 (no symptoms) to 3 (increased severity of symptoms). Item 4 Global Clinical Assessment of Akathisia rated on a 6-point scale range 0 (no symptoms) to 5 (increased severity of symptoms); higher score indicates increased severity. All rating are anchored. Only the Global Clinical Assessment of Akathisia was to be analyzed.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 6, 10, 14, 18, 22, 26, ET

End point values	Ziprasidone
Number of subjects analysed	221
Units: scores on a scale
arithmetic mean (standard deviation)
Week 1 (n=206)	0 ± 0.4
Week 2 (n=197)	0 ± 0.4
Week 6 (n=168)	0 ± 0.4
Week 10 (n=135)	0 ± 0.5
Week 14 (n=110)	0.1 ± 0.6
Week 18 (n=99)	0 ± 0.4
Week 22 (n=82)	0 ± 0.6
Week 26 (n=76)	0 ± 0.6
ET (n=127)	0 ± 0.5
Week 26 LOCF (n=206)	0.1 ± 0.5

No statistical analyses for this end point

Secondary: Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Movement Cluster Score

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End point title

Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Movement Cluster Score

End point description

AIMS: clinician rated 12-item scale to rate 7 body areas and global judgments on the severity of abnormal movements, incapacitation and subject's awareness of abnormal movements. Items 1 to 10 scored 0 (none) to 4 (severe) (total possible score 0 to 40; higher score indicates greater severity); items 11 to 14 are No or Yes response to dental status and sleep movements. Only the sum of the first 7 items to be analyzed (AIMS Movement Cluster score). Total score 0 to 28; higher score indicates greater severity. Safety Analysis Set. n=number of subjects with analyzable data at post-baseline observation. Baseline was the last available observation from Study A1281134 (EudraCT Number: 2005-005502-23) (NCT00257192). LOCF imputation used for Week 26 LOCF time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 6, 10, 14, 18, 22, 26, ET

End point values	Ziprasidone
Number of subjects analysed	221 ^[8]
Units: scores on a scale
arithmetic mean (standard deviation)
Week 1 (n=206)	0.06 ± 1.3
Week 2 (n=197)	-0.05 ± 0.7
Week 6 (n=168)	-0.04 ± 0.9
Week 10 (n=135)	0.02 ± 1.4
Week 14 (n=110)	0.01 ± 0.9
Week 18 (n=99)	0.01 ± 0.6
Week 22 (n=82)	0.1 ± 1.2
Week 26 (n=76)	0.08 ± 1.2
ET (n=127)	-0.12 ± 1.5
Week 26 LOCF (n=206)	0 ± 1

Notes
[8] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Change From Baseline in Brief Psychiatric Rating Scale - Anchored (BPRS-A) Total Score

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End point title

Change From Baseline in Brief Psychiatric Rating Scale - Anchored (BPRS-A) Total Score

End point description

BPRS-A: 18-item clinician rated scale to assess somatic concern, anxiety, emotional withdrawal, disorganization, hallucinatory behavior, guilt feelings, suspiciousness, disorientation, tension, mannerisms, posturing, grandiosity, depressive mood, hostility, motor retardation, uncooperativeness, unusual thought content, blunted affect, excitement. Ratings anchored to improve consistency for single rater over time or between raters. Items rated on 7-point scale 0 (not present) to 6 (extremely severe). Total score=sum of items (range 0 to 108); higher scores indicate increased pathology. Safety Analysis Set. n=number of subjects with analyzable data at post-baseline observation. Baseline was the last available observation from Study A1281134 (EudraCT Number: 2005-005502-23) (NCT00257192). LOCF imputation used for Week 26 LOCF time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 6, 18, 26, ET

End point values	Ziprasidone
Number of subjects analysed	220 ^[9]
Units: scores on a scale
arithmetic mean (standard deviation)
Week 2 (n=196)	-3.8 ± 7.8
Week 6 (n=167)	-6.1 ± 8.8
Week 18 (n=98)	-7.8 ± 11
Week 26 (n=75)	-8.5 ± 9.9
ET (n=127)	-4 ± 9.1
Week 26 LOCF (n=196)	-6.9 ± 8.9

Notes
[9] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Change From Baseline in Children's Global Assessment Scale (CGAS)

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End point title

Change From Baseline in Children's Global Assessment Scale (CGAS)

End point description

CGAS: 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 to 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; lower score indicates need for increased supervision. Safety Analysis Set. n=number of subjects with analyzable data at post-baseline observation. Baseline was the last available observation from Study A1281134 (EudraCT Number: 2005-005502-23) (NCT00257192). LOCF imputation used for Week 26 LOCF time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 6, 18, 26, ET

End point values	Ziprasidone
Number of subjects analysed	221 ^[10]
Units: scores on a scale
arithmetic mean (standard deviation)
Week 2 (n=197)	55.5 ± 12.9
Week 6 (n=168)	59.2 ± 12.5
Week 18 (n=99)	62.3 ± 11.4
Week 26 (n=76)	65.6 ± 12.4
ET (n=127)	56.6 ± 15.1
Week 26 LOCF (n=197)	60.5 ± 14.2

Notes
[10] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Change From Baseline in Child Health Questionnaire (CHQ)

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End point title

Change From Baseline in Child Health Questionnaire (CHQ)

End point description

CHQ: 50-item, 15 subscale parent or legal guardian assessed instrument of child's physical, emotional, social well-being, and relative burden of disease on the parents; rated on Likert-type scale: range 0 to 100; higher scores indicate a more positive health status. Global indicators for Physical Health and Psychosocial Health are weighted composites derived from subscale items using scoring algorithms (transformed scores); range 0 to 100: higher scores indicate more positive health status. Safety Analysis Set. n=number of subjects with analyzable data at post-baseline observation. Baseline was the last available observation from Study A1281134 (EudraCT Number: 2005-005502-23) (NCT00257192). LOCF imputation used for Week 26 LOCF time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 6 and 26, ET

End point values	Ziprasidone
Number of subjects analysed	220 ^[11]
Units: scores on a scale
arithmetic mean (standard deviation)
Global Health: Week 6 (n=163)	44.2 ± 23.9
Global Health: Week 26 (n=75)	50.3 ± 22.1
Global Health: ET (n=124)	40.5 ± 25.8
Global Health: Week 26 LOCF (n=164)	44.9 ± 22.9
Global Behavior: Week 6 (n=163)	44.9 ± 23.6
Global Behavior: Week 26 (n=75)	47 ± 24.2
Global Behavior: ET (n=124)	38.7 ± 25.8
Global Behavior: Week 26 LOCF (n=164)	43.8 ± 24.4
Family Cohesion: Week 6 (n=163)	53 ± 23.9
Family Cohesion: Week 26 (n=75)	54.4 ± 24.7
Family Cohesion: ET (n=124)	50 ± 23.9
Family Cohesion: Week 26 LOCF (n=164)	53.4 ± 23.7
Physical Health: Week 6 (n=163)	76.4 ± 30.8
Physical Health: Week 26 (n=74)	80.2 ± 28.8
Physical Health: ET (n=123)	75.5 ± 32.8
Physical Health: Week 26 LOCF (n=163)	77.8 ± 31.2
Bodily Pain: Week 6 (n=163)	80.8 ± 21.6
Bodily Pain: Week 26 (n=75)	84.4 ± 21.5
Bodily Pain: ET (n=124)	81 ± 22.7
Bodily Pain: Week 26 LOCF (n=164)	82.5 ± 21.3
Emotion, Behavior: Week 6 (n=163)	53.3 ± 32.6
Emotion, Behavior: Week 26 (n=74)	60.1 ± 31.2
Emotion, Behavior: ET (n=123)	49.5 ± 34.5
Emotion, Behavior: Week 26 LOCF (n=163)	54.8 ± 32.2
Time Impact on Parent: Week 6 (n=163)	62 ± 26.6
Time Impact on Parent: Week 26 (n=75)	69.9 ± 23.5
Time Impact on Parent: ET (n=124)	59.9 ± 28.6
Time Impact on Parent: Week 26 LOCF (n=164)	65.1 ± 26.3
Emotional Impact on Parent: Week 6 (n=163)	49.5 ± 24.6
Emotional Impact on Parent: Week 26 (n=75)	57.2 ± 24.7
Emotional Impact on Parent: ET (n=124)	43.4 ± 25.9
Emotional Impact on Parent: Week 26 LOCF (n=164)	52.2 ± 26
Mental Health: Week 6 (n=163)	63.6 ± 16.1
Mental Health: Week 26 (n=75)	66.7 ± 16.5
Mental Health: ET (n=124)	60.8 ± 18.3
Mental Health: Week 26 LOCF (n=164)	65.1 ± 16.1
Physical Function: Week 6 (n=163)	80.4 ± 22.3
Physical Function: Week 26 (n=75)	84.9 ± 19
Physical Function: ET (n=124)	79.5 ± 23.4
Physical Function: Week 26 LOCF (n=164)	81.4 ± 21.9
Behavior Scale: Week 6 (n=163)	62.7 ± 16.8
Behavior Scale: Week 26 (n=75)	64.5 ± 20
Behavior Scale: ET (n=124)	60.2 ± 18.7
Behavior Scale: Week 26 LOCF (n=164)	63 ± 18.4
Self-Esteem: Week 6 (n=163)	52.7 ± 20.3
Self-Esteem: Week 26 (n=74)	55.3 ± 21
Self-Esteem: ET (n=124)	52.6 ± 21.7
Self-Esteem: Week 26 LOCF (n=163)	54.5 ± 20.6
General Health Perception: Week 6 (n=163)	50.3 ± 15.3
General Health Perception: Week 26 (n=75)	51.8 ± 16.4
General Health Perception: ET (n=124)	49.7 ± 15.1
General Health Perception: Week 26 LOCF (n=164)	50.3 ± 15.4
Family Activities: Week 6 (n=163)	60.1 ± 24.9
Family Activities: Week 26 (n=75)	63.9 ± 24.1
Family Activities: ET (n=124)	56.3 ± 27.6
Family Activities: Week 26 LOCF (n=164)	61.6 ± 26.1
Physical Health Global Subscale: Week 6 (n=163)	44.1 ± 11.7
Physical Health Global Subscale: Week 26 (n=74)	46.6 ± 10.9
Physical Health Global: ET (n=123)	43.8 ± 12.9
Physical Health Global: Week 26 LOCF (n=163)	44.8 ± 12.2
Psychosocial Health Global: Week 6 (n=163)	35.7 ± 10.4
Psychosocial Health Global: Week 26 (n=74)	38.5 ± 10.9
Psychosocial Health Global: ET (n=123)	33.7 ± 11.9
Psychosocial Health Global: Week 26 LOCF (n=163)	36.8 ± 10.7

Notes
[11] - N=number of subjects with analyzable data at baseline.

No statistical analyses for this end point

Secondary: Number of Subjects Per Response on the School Placement Questionnaire: School Situation

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End point title

Number of Subjects Per Response on the School Placement Questionnaire: School Situation

End point description

School placement questionnaire: parent or legal guardian assessed questionnaire to determine whether the child is currently enrolled in school (or planned to be enrolled if on school holiday like summer break), whether attending regularly if enrolled, and how well the child is doing overall in school. Questions were modified from those used in the National Institute of Mental Health (NIMH) funded Treatment of Early Onset Schizophrenia Spectrum (TEOSS) study. Results determine whether subjects are currently attending school and qualitatively describe how well they are doing in school. Safety Analysis Set. n=number of subjects with analyzable data at baseline and post-baseline observation. Baseline was the last available observation from Study A1281134 (EudraCT Number: 2005-005502-23) (NCT00257192). LOCF imputation used for Week 26 LOCF time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 6 and 26, ET

End point values	Ziprasidone
Number of subjects analysed	221 ^[12]
Units: subjects
Baseline: Enrolled or Attend (n=221)	63
Baseline: Not Attend or Mental Illness (n=221)	59
Baseline: Not Attend or Other (n=221)	4
Baseline: Enrolled or Vacation (n=221)	26
Baseline: Not Enrolled or Mental Illness (n=221)	42
Baseline: Not Enrolled or Other (n=221)	27
Week 6: Enrolled or Attend (n=166)	68
Week 6: Not Attend or Mental Illness (n=166)	32
Week 6: Not Attend or Other (n=166)	1
Week 6: Enrolled or Vacation (n=166)	14
Week 6: Not Enrolled or Mental Illness (n=166)	29
Week 6: Not Enrolled or Other (n=166)	22
Week 26: Enrolled or Attend (n=75)	35
Week 26: Not Attend or Mental Illness (n=75)	9
Week 26: Not Attend or Other (n=75)	0
Week 26: Enrolled or Vacation (n=75)	5
Week 26: Not Enrolled or Mental Illness (n=75)	13
Week 26: Not Enrolled or Other (n=75)	13
ET: Enrolled or Attend (n=125)	42
ET: Not Attend or Mental Illness (n=125)	35
ET: Not Attend or Other (n=125)	1
ET: Enrolled or Vacation (n=125)	9
ET: Not Enrolled or Mental Illness (n=125)	21
ET: Not Enrolled or Other (n=125)	17
Week 26 LOCF: Enrolled or Attend (n=166)	75
Week 26 LOCF: Not Attend or Mental Illness (n=166)	30
Week 26 LOCF: Not Attend or Other (n=166)	1
Week 26 LOCF: Enrolled or Vacation (n=166)	8
Week 26 LOCF: Not Enrolled/Mental Illness (n=166)	28
Week 26 LOCF: Not Enrolled or Other (n=166)	24

Notes
[12] - N=number of subjects analyzable for School Placement Questionnaire.

No statistical analyses for this end point

Secondary: Number of Subjects Per Response on the School Placement Questionnaire: School Attendance

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End point title

Number of Subjects Per Response on the School Placement Questionnaire: School Attendance

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 6 and 26, ET

End point values	Ziprasidone
Number of subjects analysed	133 ^[13]
Units: subjects
Baseline: No Absences (n=133)	25
Baseline: Only a Few Absences (n=133)	37
Baseline: Frequent Absences (n=133)	12
Baseline: Did Not Attend (n=133)	36
Baseline: Not Applicable or Vacation (n=133)	23
Week 6: No Absences (n=95)	31
Week 6: Only a Few Absences (n=95)	29
Week 6: Frequent Absences (n=95)	11
Week 6: Did Not Attend (n=95)	10
Week 6: Not Applicable or Vacation (n=95)	14
Week 26: No Absences (n=42)	14
Week 26: Only a Few Absences (n=42)	16
Week 26: Frequent Absences (n=42)	7
Week 26: Did Not Attend (n=42)	0
Week 26: Not Applicable or Vacation (n=42)	5
ET: No Absences (n=62)	16
ET: Only a Few Absences (n=62)	23
ET: Frequent Absences (n=62)	5
ET: Did Not Attend (n=62)	11
ET: Not Applicable or Vacation (n=62)	7
Week 26 LOCF: No Absences (n=93)	32
Week 26 LOCF: Only a Few Absences (n=93)	32
Week 26 LOCF: Frequent Absences (n=93)	14
Week 26 LOCF: Did Not Attend (n=93)	7
Week 26 LOCF: Not Applicable or Vacation (n=93)	8

Notes
[13] - N=number of subjects analyzable for School Placement Questionnaire.

No statistical analyses for this end point

Secondary: Number of Subjects Per Response on the School Placement Questionnaire: Overall School Performance

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End point title

Number of Subjects Per Response on the School Placement Questionnaire: Overall School Performance

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 6 and 26, ET

End point values	Ziprasidone
Number of subjects analysed	103 ^[14]
Units: subjects
Baseline: Excellent (n=103)	5
Baseline: Good (n=103)	25
Baseline: Fair (n=103)	40
Baseline: Poor (n=103)	23
Baseline: Very Poor (n=103)	10
Week 6: Excellent (n=73)	2
Week 6: Good (n=73)	23
Week 6: Fair (n=73)	34
Week 6: Poor (n=73)	14
Week 6: Very Poor (n=73)	0
Week 26: Excellent (n=37)	1
Week 26: Good (n=37)	10
Week 26: Fair (n=37)	18
Week 26: Poor (n=37)	5
Week 26: Very Poor (n=37)	3
ET: Excellent (n=48)	0
ET: Good (n=48)	15
ET: Fair (n=48)	23
ET: Poor (n=48)	6
ET: Very Poor (n=48)	4
Week 26 LOCF: Excellent (n=80)	1
Week 26 LOCF: Good (n=80)	22
Week 26 LOCF: Fair (n=80)	39
Week 26 LOCF: Poor (n=80)	15
Week 26 LOCF: Very Poor (n=80)	3

Notes
[14] - N=number of subjects analyzable for School Placement Questionnaire.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Treatment emergent adverse events are reported from time of first dose of study treatment up to 6 days after last dose of study treatment.

Adverse event reporting additional description

Safety population= all randomized subjects with at least 1 dose of study treatment. An Adverse Event (AE) term may be reported as both a serious and non-serious AE, but are distinct events. AE may= serious for 1 subject and= non-serious for another subject or subject may have experienced both serious and non-serious episode of the same event.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

0.0

Reporting group title

Ziprasidone

Reporting group description

Titrated over a 2-week period, starting with an evening dose of 20 mg/day, and subsequent dose increases of 20 mg/day every second day up to a target dose of 80 to 160 mg/day for subjects weighing >=45 kg. For subjects with a body weight <45 kg, the maximum permitted dose was 80 mg/day (40 mg BID). Doses could have been reduced to a minimum of 40 mg/day (20 mg BID).

Serious adverse events	Ziprasidone
Total subjects affected by serious adverse events
subjects affected / exposed	16 / 221 (7.24%)
number of deaths (all causes)	1
number of deaths resulting from adverse events	1
Nervous system disorders
Dystonia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
General disorders and administration site conditions
Drug ineffective
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Social circumstances
Sexual activity increased
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Victim of sexual abuse
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Psychiatric disorders
Aggression
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Agitation
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Anxiety
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Completed suicide
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	1 / 1
Delusional perception
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hallucination
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hallucination, auditory
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Intentional self-injury
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Major depression
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Obsessive-compulsive disorder
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Persecutory delusion
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Schizophrenia
alternative assessment type: Non-systematic
subjects affected / exposed	4 / 221 (1.81%)
occurrences causally related to treatment / all	0 / 4
deaths causally related to treatment / all	0 / 0
Schizophrenia, paranoid type
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Self injurious behaviour
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Suicidal behaviour
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Suicidal ideation
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 221 (1.36%)
occurrences causally related to treatment / all	0 / 3
deaths causally related to treatment / all	0 / 0
Thinking abnormal
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Ziprasidone
Total subjects affected by non serious adverse events
subjects affected / exposed	55 / 221 (24.89%)
Nervous system disorders
Headache
alternative assessment type: Non-systematic
subjects affected / exposed	20 / 221 (9.05%)
occurrences all number	35
Somnolence
alternative assessment type: Non-systematic
subjects affected / exposed	33 / 221 (14.93%)
occurrences all number	38
Tremor
alternative assessment type: Non-systematic
subjects affected / exposed	14 / 221 (6.33%)
occurrences all number	21

More information

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Were there any global substantial amendments to the protocol? Yes

06 Dec 2006

1. Electrocardiograms (ECGs) showing a Fridericia corrected QT (QTcF) of >=460 milliseconds (msec) or a suspected increase from baseline of 60 msec or greater was to be repeated within the same visit. If the QTcF value persisted at >=460 msec and/or the change from baseline. persisted at >=60 msec, the study drug was to be discontinued immediately and a pediatric cardiologist or a pediatric intensive care specialist should be contacted to discuss the ECG result. 2. Waist Circumference evaluation, fasting glucose and Glycosylated hemoglobin (HbA1c) as clinical laboratory testing and Possibly Suicide-Related Adverse Events (PSRAEs) monitoring were included. 4. Benzhexol, other anticholinergics and Steroids (except inhaled, if taken at least 2 months before study with stable dose and clinical condition) were included in concomitant medications. 5. It was recommended that subjects should complete the Central nervous system (CNS) Vital Signs battery before any intrusive assessments such as blood draws, if at all possible. 6. Exposure In utero definition was amended to include paternal exposure. 7. 8. For safety, for those subjects who were randomized to placebo in the double-blind study, baseline values was to be the observation prior to dosing for ECG and blood pressure/pulse only, initiating dosing in the open-label extension study.

17 Jan 2007

1. To assess risks related to the possible prolongation of the QT interval, subjects with QTcF ≥440 460 msec or with risk factors for QT prolongation were to be excluded. Extensive ECG monitoring was to be performed throughout the study, including triplicate ECGs at baseline (3 timepoints). 2. Concomitant medication section amended to include trihexyphenidyl hydrochloride (HCl) and exclude Benzhexol.

13 Nov 2007

1. Trial treatment section was amended to include drug blister card design to decrease the chance for dosing errors (usually overdosing).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The AE tables were amended to incorporate previously unreported AEs that were found during an independent audit and verified by the investigators.

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Clinical trials

Clinical Trial Results: 26-week open-label extension study evaluating the safety and tolerability of flexible doses of oral ziprasidone in adolescent subjects with schizophrenia.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Subjects With Change From Baseline to Each Pubertal Stage of Development as Assessed by the Tanner Adolescent Pubertal Self Assessment

Secondary: Number of Subjects With Change From Baseline to Each Pubertal Stage of Development as Assessed by the Tanner Adolescent Pubertal Self Assessment

Secondary: Change From Baseline in Children's Problem Behavior and Aggression Questionnaire (CPBAQ) Total Score

Secondary: Change From Baseline in Children's Problem Behavior and Aggression Questionnaire (CPBAQ) Total Score

Secondary: Change From Baseline in Child Depression Rating Scale - Revised (CDRS-R): Total Score

Secondary: Change From Baseline in Child Depression Rating Scale - Revised (CDRS-R): Total Score

Secondary: Change From Baseline in Central Nervous System (CNS) Vital Signs Cognitive Test Battery (Includes Sedation Item): Subscales

Secondary: Change From Baseline in Central Nervous System (CNS) Vital Signs Cognitive Test Battery (Includes Sedation Item): Subscales

Secondary: Change From Baseline in CNS Vital Signs Cognitive Test Battery: Neurocognitive Index

Secondary: Change From Baseline in CNS Vital Signs Cognitive Test Battery: Neurocognitive Index

Secondary: Change From Baseline in Simpson-Angus Rating Scale (SARS)

Secondary: Change From Baseline in Simpson-Angus Rating Scale (SARS)

Secondary: Change From Baseline in Barnes Akathisia Rating Scale (BAS) Global Clinical Assessment Item

Secondary: Change From Baseline in Barnes Akathisia Rating Scale (BAS) Global Clinical Assessment Item

Secondary: Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Movement Cluster Score

Secondary: Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Movement Cluster Score

Secondary: Change From Baseline in Brief Psychiatric Rating Scale - Anchored (BPRS-A) Total Score

Secondary: Change From Baseline in Brief Psychiatric Rating Scale - Anchored (BPRS-A) Total Score

Secondary: Change From Baseline in Children's Global Assessment Scale (CGAS)

Secondary: Change From Baseline in Children's Global Assessment Scale (CGAS)

Secondary: Change From Baseline in Child Health Questionnaire (CHQ)

Secondary: Change From Baseline in Child Health Questionnaire (CHQ)

Secondary: Number of Subjects Per Response on the School Placement Questionnaire: School Situation

Secondary: Number of Subjects Per Response on the School Placement Questionnaire: School Situation

Secondary: Number of Subjects Per Response on the School Placement Questionnaire: School Attendance

Secondary: Number of Subjects Per Response on the School Placement Questionnaire: School Attendance

Secondary: Number of Subjects Per Response on the School Placement Questionnaire: Overall School Performance

Secondary: Number of Subjects Per Response on the School Placement Questionnaire: Overall School Performance

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
26-week open-label extension study evaluating the safety and tolerability of flexible doses of oral ziprasidone in adolescent subjects with schizophrenia.