Safety and Tolerability of Ziprasidone in Children and Adolescents With Bipolar I Disorder (Manic or Mixed)

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 (Manic Or Mixed)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00265330

Enrollment

169

Registered

2005-12-14

Start date

2006-03-31

Completion date

2008-01-31

Last updated

2021-03-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Bipolar Disorder

Keywords

Children And Adolescents With Bipolar I Disorder (Manic Or Mixed)

Brief summary

The purpose of this study is to assess the safety and tolerability of ziprasidone during long-term open-label administration in children and adolescents (ages 10-17) with bipolar I disorder (manic or mixed)

Interventions

DRUGZiprasidone oral capsules

Study medications will include oral ziprasidone capsules of 20 mg, 40 mg, 60 mg, and 80 mg strength. Subjects will be dosed daily for 26 weeks using a flexible dose design with a minimal dose range of 20mg bid to a maximum dose range of 80 mg bid .

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

10 Years to 17 Years

Healthy volunteers

Inclusion criteria

* Participation in double-blind treatment study A1281132, meeting specific criteria of duration and safety

Exclusion criteria

* Imminent risk of suicide or homicide, as judged by the site investigator;serious adverse event related to study medication in study A1281132; significant prolongation of QT interval in study A1281132.

Design outcomes

Primary

Measure	Time frame	Description
Young Mania Rating Scale (YMRS) Total Score Change From Baseline	baseline and 26 Weeks; 26 Weeks Last Observation Carried Forward (LOCF)	YMRS: 11-item instrument with scales 0 (normal) to 4 (highest abnormal)for 7 items and 0 (normal) to 8 (highest abnormal) for 4 items. Total possible 0 - 60. Baseline is from parent study A1281132.
Clinical Global Impression of Severity (CGI-S) Change From Baseline	baseline and 26 Weeks; 26 Weeks LOCF	CGI-S Scale:standardized assessment tool to rate severity of subject's illness; assesses investigator's impression of subject's current illness state. Change: score at observation minus score at baseline. Score: 1 (not ill at all) to 7 (among most extremely ill). Baseline = last available observation from parent double-blind study(A1281132).
Incidence of Lab Abnormalities	Week 26	number of subjects with an abnormal lab value for those parameters with 5% or greater incidence of abnormality.
Change in Low-Density Lipoprotein (LDL) Cholesterol and Fasting Cholesterol	Week 6, Week 26	Mean Change: lab value at observation minus lab value at baseline.
Change in Hormones	Week 6, Week 26	Mean Change: lab value at observation minus lab value at baseline
Mean Change From Baseline in Supine Systolic Blood Pressure	Week 1 through Week 26	Mean Change: vital sign value at observation minus vital sign value at baseline
Mean Change From Baseline in Supine Diastolic Blood Pressure	Week 1 through Week 26	Mean Change: vital sign value at observation minus vital sign value at baseline
Mean Change From Baseline in Supine Pulse Rates	Week 1 through Week 26	Mean Change: vital sign value at observation minus vital sign value at baseline
Mean Change From Baseline in Standing Systolic Blood Pressure	Week 1 through Week 26	Mean Change: vital sign value at observation minus vital sign value at baseline
Mean Change From Baseline in Standing Diastolic Blood Pressure	Week 1 through Week 26	Mean Change: vital sign value at observation minus vital sign value at baseline
Mean Change From Baseline in Standing Pulse Rates	Week 1 through Week 26	Mean Change: vital sign value at observation minus vital sign value at baseline
Mean Change From Baseline for Body Weight	Week 6, Week 26	Mean change; body weight value at observation minus body weight value at baseline.
Mean Change From Baseline for Body Mass Index (BMI) Z-Score	Week 6, 26, early termination	mean change in body weight BMI -Z score calculated by subtracting median reference value of the population from observed value and dividing by standard deviation of reference population (kg/m squared). 0=no change
Body Mass Index (BMI) Z-score Frequency	Week 6	change in body weight BMI -Z score calculated by subtracting median reference value of the population from observed value and dividing by standard deviation of reference population (kg/m squared). 0=no change
Mean Change From Baseline for QTcF Intervals	Baseline to Week 26 (end of study)	QT intervals (observed in an electrocardiogram)corrected using Fridericia's formula (QTcF). Mean change: mean change of observation minus baseline. Baseline: last available observation in the parent double-blind study.
Frequency of Largest Categorical Increases in QTcF for Males	Week 26 (end of study)	QT intervals (observed in an electrocardiogram) corrected with Fridericia's Formula (QTcF). Number of subjects with corresponding categorical increase in QTcF.
Frequency of Largest Categorical Increases in QTcF for Females	Week 26 (end of study)	QT interval (observed in an electrocardiogram) corrected using Fridericia Formula (QTcF). Number of subjects with corresponding categorical increase in QTcF.
Frequency of Largest Categorical Increases in QTcF - All Subjects	Week 26 (end of study)	QT intervals (observed in an electrocardiogram)corrected using Fridericia Formula (QTcF). Number of subjects with corresponding categorical increase in QTcF.

Countries

United States

Participant flow

Recruitment details

The number of subjects entering this trial was determined by the number of subjects electing to continue treatment after completing or withdrawing from the preceding double-blind study (A1281132: NCT00257166).

Pre-assignment details

A total of 169 subjects from the parent study were assigned to the extension study and 162 continued on and received study treatment in the extension study.

Participants by arm

Arm	Count
Ziprasidone Dosing was flexible, with dosing adjustments made at the discretion of the investigator to maintain optimal efficacy and tolerability. For subjects having a body weight of 45 kilograms (kg) or greater, the target dosage range was 40-80 milligrams (mg) twice per day (BID) (80-160 mg/day). For subjects having a body weight under 45 kg, the maximum permitted dose was 80 mg/day (40 mg BID).	162
Total	162

Arm

Count

Ziprasidone

Dosing was flexible, with dosing adjustments made at the discretion of the investigator to maintain optimal efficacy and tolerability. For subjects having a body weight of 45 kilograms (kg) or greater, the target dosage range was 40-80 milligrams (mg) twice per day (BID) (80-160 mg/day). For subjects having a body weight under 45 kg, the maximum permitted dose was 80 mg/day (40 mg BID).

162

Total

162

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	41
Overall Study	Began Taking Formulary Geodon	1
Overall Study	Discharged from Unit for Long Term Care	1
Overall Study	Family Scheduling Conflicts	1
Overall Study	Lack of Efficacy	4
Overall Study	Lost to Follow-up	8
Overall Study	Patient Wanted to Start Psychotherapy	1
Overall Study	Principal Investigators Request	1
Overall Study	Protocol Violation	1
Overall Study	Site Closed by Sponsor	1
Overall Study	Withdrawal by Subject	34
Overall Study	Withdrew Consent	1

Baseline characteristics

Characteristic	Ziprasidone
Age, Continuous	13.3 years STANDARD_DEVIATION 2.1
Sex: Female, Male Female	72 Participants
Sex: Female, Male Male	90 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	123 / 162
serious Total, serious adverse events	17 / 162

Outcome results

Primary

Body Mass Index (BMI) Z-score Frequency

change in body weight BMI -Z score calculated by subtracting median reference value of the population from observed value and dividing by standard deviation of reference population (kg/m squared). 0=no change

Time frame: Week 26

Arm	Measure	Group	Value (NUMBER)
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	<-4	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥-4 to <-3	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥-3 to <-2	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥-2 to <-1	1 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥-1 to <0	27 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥0 to <1	39 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥1 to <2	1 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥2 to <3	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥3 to <4	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥4	0 participants

Primary

Body Mass Index (BMI) Z-score Frequency

Time frame: Week 6

Arm	Measure	Group	Value (NUMBER)
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	<-4	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥-2 to <-1	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥-1 to <0	53 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥0 to <1	61 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥-4 to <-3	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥-3 to <-2	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥1 to <2	1 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥2 to <3	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥3 to <4	0 participants
Ziprasidone	Body Mass Index (BMI) Z-score Frequency	≥4	0 participants

Primary

Change in Hormones

Mean Change: lab value at observation minus lab value at baseline

Time frame: Week 6, Week 26

Population: The Safety Analysis Set includes all subjects who took at least one dose of study medication in this open-label extension study. (Row: n= total number of subjects with at least 1 observation of the given laboratory test.)

Arm	Measure	Group	Value (MEAN)	Dispersion
Ziprasidone	Change in Hormones	Testosterone Week 6 (n=80)	0.9 nanogram/deciliter (ng/dL)	Standard Deviation 84.3
Ziprasidone	Change in Hormones	Testosterone Week 26 (n=38)	-23.4 nanogram/deciliter (ng/dL)	Standard Deviation 112.9
Ziprasidone	Change in Hormones	Testosterone Early Termination (n=32)	-0.4 nanogram/deciliter (ng/dL)	Standard Deviation 61.8
Ziprasidone	Change in Hormones	Prolactin Week 6 (n=110)	2.7 nanogram/deciliter (ng/dL)	Standard Deviation 13.2
Ziprasidone	Change in Hormones	Prolactin Week 26 (n=59)	1.9 nanogram/deciliter (ng/dL)	Standard Deviation 8.5
Ziprasidone	Change in Hormones	Prolactin Early Termination (n=40)	1.0 nanogram/deciliter (ng/dL)	Standard Deviation 11.6
Ziprasidone	Change in Hormones	Insulin-like growth factor Week 6 (n=95)	-19.9 nanogram/deciliter (ng/dL)	Standard Deviation 63.4
Ziprasidone	Change in Hormones	Insulin-like growth factor Week 26 (n=47)	-9.2 nanogram/deciliter (ng/dL)	Standard Deviation 68.1
Ziprasidone	Change in Hormones	Insulin-like growth factor Early Term (n=34)	-8.4 nanogram/deciliter (ng/dL)	Standard Deviation 66.5

Primary

Change in Low-Density Lipoprotein (LDL) Cholesterol and Fasting Cholesterol

Mean Change: lab value at observation minus lab value at baseline.

Time frame: Week 6, Week 26

Arm	Measure	Group	Value (MEAN)	Dispersion
Ziprasidone	Change in Low-Density Lipoprotein (LDL) Cholesterol and Fasting Cholesterol	LDL cholesterol Week 6 (n=113)	-7.5 milligram /deciliter (mg/dL)	Standard Deviation 19.7
Ziprasidone	Change in Low-Density Lipoprotein (LDL) Cholesterol and Fasting Cholesterol	LDL cholesterol Week 26 (n=59)	-8.9 milligram /deciliter (mg/dL)	Standard Deviation 19.5
Ziprasidone	Change in Low-Density Lipoprotein (LDL) Cholesterol and Fasting Cholesterol	LDL cholesterol Early Termination (n=44)	-7.6 milligram /deciliter (mg/dL)	Standard Deviation 20.1
Ziprasidone	Change in Low-Density Lipoprotein (LDL) Cholesterol and Fasting Cholesterol	Fasting cholesterol Week 6 (n=113)	-7.7 milligram /deciliter (mg/dL)	Standard Deviation 21.8
Ziprasidone	Change in Low-Density Lipoprotein (LDL) Cholesterol and Fasting Cholesterol	Fasting cholesterol Week 26 (n=59)	-10.3 milligram /deciliter (mg/dL)	Standard Deviation 22.7
Ziprasidone	Change in Low-Density Lipoprotein (LDL) Cholesterol and Fasting Cholesterol	Fasting cholesterol Early Termination (n=44)	-8.6 milligram /deciliter (mg/dL)	Standard Deviation 24.9

Primary

Clinical Global Impression of Severity (CGI-S) Change From Baseline

CGI-S Scale:standardized assessment tool to rate severity of subject's illness; assesses investigator's impression of subject's current illness state. Change: score at observation minus score at baseline. Score: 1 (not ill at all) to 7 (among most extremely ill). Baseline = last available observation from parent double-blind study(A1281132).

Time frame: baseline and 26 Weeks; 26 Weeks LOCF

Population: The Safety Analysis Set includes all subjects who took at least one dose of study medication in this open-label extension study. (Row: n=number subjects with observation)

Arm	Measure	Group	Value (MEAN)	Dispersion
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Week 10 (n=99)	-0.7 score on scale	Standard Deviation 1.3
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Week 14 (n=85)	-0.7 score on scale	Standard Deviation 1.2
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Week 18 (n=76)	-0.7 score on scale	Standard Deviation 1.5
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Week 22 (n=70)	-0.8 score on scale	Standard Deviation 1.3
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Week 26 (n=69)	-1.1 score on scale	Standard Deviation 1.4
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Early Termination (n=48)	0.4 score on scale	Standard Deviation 1.1
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Week 26-LOCF (n=160)	-0.4 score on scale	Standard Deviation 1.3
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Week 1 (n=159)	-0.2 score on scale	Standard Deviation 0.9
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Week 2 (n=150)	-0.5 score on scale	Standard Deviation 1.2
Ziprasidone	Clinical Global Impression of Severity (CGI-S) Change From Baseline	Week 6 (n=122)	-0.4 score on scale	Standard Deviation 1.1

Primary

Frequency of Largest Categorical Increases in QTcF - All Subjects

QT intervals (observed in an electrocardiogram)corrected using Fridericia Formula (QTcF). Number of subjects with corresponding categorical increase in QTcF.

Time frame: Week 26 (end of study)

Arm	Measure	Group	Value (NUMBER)
Ziprasidone	Frequency of Largest Categorical Increases in QTcF - All Subjects	≥480 msec	0 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF - All Subjects	≥450 msec (millisecond)	3 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF - All Subjects	≥460 msec	0 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF - All Subjects	≥30 msec increase	38 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF - All Subjects	≥60 msec increase	2 participants

Primary

Frequency of Largest Categorical Increases in QTcF for Females

QT interval (observed in an electrocardiogram) corrected using Fridericia Formula (QTcF). Number of subjects with corresponding categorical increase in QTcF.

Time frame: Week 26 (end of study)

Arm	Measure	Group	Value (NUMBER)
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Females	≥460 msec	0 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Females	≥480 msec	0 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Females	≥450 msec (millisecond)	3 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Females	≥30 msec increase	10 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Females	≥60 msec increase	2 participants

Primary

Frequency of Largest Categorical Increases in QTcF for Males

QT intervals (observed in an electrocardiogram) corrected with Fridericia's Formula (QTcF). Number of subjects with corresponding categorical increase in QTcF.

Time frame: Week 26 (end of study)

Arm	Measure	Group	Value (NUMBER)
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Males	≥450 msec (millisecond )	0 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Males	≥460 msec	0 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Males	≥480 msec	0 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Males	≥30 msec increase	28 participants
Ziprasidone	Frequency of Largest Categorical Increases in QTcF for Males	≥60 msec increase	0 participants

Primary

Incidence of Lab Abnormalities

number of subjects with an abnormal lab value for those parameters with 5% or greater incidence of abnormality.

Time frame: Week 26

Population: Total number of subjects with given laboratory test at given visit. Range: N=136-134, with the exception of Insulin (N=115)

Arm	Measure	Group	Value (NUMBER)
Ziprasidone	Incidence of Lab Abnormalities	Urine specific gravity (N=136)	13 participants
Ziprasidone	Incidence of Lab Abnormalities	Urine red blood cells (N=136)	13 participants
Ziprasidone	Incidence of Lab Abnormalities	Monocytes (N=134)	9 participants
Ziprasidone	Incidence of Lab Abnormalities	Triglycerides (N=136)	10 participants
Ziprasidone	Incidence of Lab Abnormalities	Bicarbonate (N=136)	44 participants
Ziprasidone	Incidence of Lab Abnormalities	Urine blood/Hemoglobin (N=136)	34 participants
Ziprasidone	Incidence of Lab Abnormalities	Urine ketones (N=136)	32 participants
Ziprasidone	Incidence of Lab Abnormalities	Testosterone (N=134)	22 participants
Ziprasidone	Incidence of Lab Abnormalities	Urine white blood cells (N=136)	10 participants
Ziprasidone	Incidence of Lab Abnormalities	Insulin (N=115)	8 participants

Primary

Mean Change From Baseline for Body Mass Index (BMI) Z-Score

mean change in body weight BMI -Z score calculated by subtracting median reference value of the population from observed value and dividing by standard deviation of reference population (kg/m squared). 0=no change

Time frame: Week 6, 26, early termination

Arm	Measure	Group	Value (MEAN)	Dispersion
Ziprasidone	Mean Change From Baseline for Body Mass Index (BMI) Z-Score	Week 26 (n=68)	0.1 score on scale	Standard Deviation 0.5
Ziprasidone	Mean Change From Baseline for Body Mass Index (BMI) Z-Score	Early Termination (n=74)	0.0 score on scale	Standard Deviation 0.3
Ziprasidone	Mean Change From Baseline for Body Mass Index (BMI) Z-Score	Week 6 (n=119)	0.0 score on scale	Standard Deviation 0.3

Primary

Mean Change From Baseline for Body Weight

Mean change; body weight value at observation minus body weight value at baseline.

Time frame: Week 6, Week 26

Arm	Measure	Group	Value (MEAN)	Dispersion
Ziprasidone	Mean Change From Baseline for Body Weight	Week 6 (n=119)	1.3 kilogram	Standard Deviation 3
Ziprasidone	Mean Change From Baseline for Body Weight	Week 26 (n=68)	3.9 kilogram	Standard Deviation 5.4
Ziprasidone	Mean Change From Baseline for Body Weight	Early Termination (n=74)	1.4 kilogram	Standard Deviation 2.8

Primary

Mean Change From Baseline for QTcF Intervals

QT intervals (observed in an electrocardiogram)corrected using Fridericia's formula (QTcF). Mean change: mean change of observation minus baseline. Baseline: last available observation in the parent double-blind study.

Time frame: Baseline to Week 26 (end of study)

Arm	Measure	Group	Value (MEAN)	Dispersion
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Week 26 (n=64)	7.1 millisecond	Standard Deviation 15.2
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Week 1 (n=152)	4.8 millisecond	Standard Deviation 18.5
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Week 2 (n=137)	3.5 millisecond	Standard Deviation 17.7
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Week 6/pre-dose (n=111)	7.6 millisecond	Standard Deviation 17.7
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Week 6/5-7 hours post dose (n=107)	7.0 millisecond	Standard Deviation 18.4
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Week 10 (n=91)	4.3 millisecond	Standard Deviation 18.8
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Week 14 (n=81)	6.2 millisecond	Standard Deviation 17.4
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Week 18 (n=73)	7.4 millisecond	Standard Deviation 15.4
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Week 22 (n=68)	8.1 millisecond	Standard Deviation 16.1
Ziprasidone	Mean Change From Baseline for QTcF Intervals	Early Termination (n=45)	2.7 millisecond	Standard Deviation 17

Primary