Extension Study Evaluating The Safety And Tolerability Of Flexible Doses Of Oral Ziprasidone In Children And Adolescents With Bipolar I Disorder

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Ziprasidone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Evidence of personally signed and dated informed consent document by the legal representative and an assent document by the subject . Subjects and their legal guardians who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. The subjects must have received investigational product in Study A1281198 before entering this open label extension. In the investigator's opinion, the subject must be likely to benefit from antipsychotic therapy . 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 Exclusion Criteria 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. Subjects requiring any medications not allowed by the Concomitant Medication Table 12 (see Concomitant Treatment(s)). Subjects who require treatment with drugs that are known to consistently prolong the QT interval (see Concomitant Medication Table 12). Subjects who are judged by the investigator as being at imminent risk of suicide. 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). 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. Pregnant female subjects, breastfeeding female subjects. Participation in other studies other than the preceding Study. 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.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Subjects would completed A1281198 will be transitioned under double blind conditions to 26 weeks of treatment with flexibly dosed opened label ziprasidone.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ziprasidone<br>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. | Drug: Ziprasidone<br>* 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.<br>Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study medication without regard to possibility of causal relationship to it. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/ incapacity; congenital anomaly. AEs included both serious and all non-serious AEs. | A1281201: Day 1 up to 35 days after last dose of study medication (maximum up to 31 Weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Laboratory Abnormalities | Hemoglobin (Hg), hematocrit, erythrocytes: <0.8*lower limits of normal (LLN); platelets: <0.5*LLN>1.75*upper limits of normal (ULN); leukocytes (leu), glucose-fasting:<0.6*LLN>1.5*ULN; lymphocytes (lym), lym/leu, neutrophils (neu), neu/leu, protein, albumin, phosphate, free thyroxine, thyroid stimulating hormone: <0.8*LLN>1.2*ULN; basophils (bas), bas/leu, eosinophils (eos), eos/leu, monocytes(mon), mon/leu: >1.2*ULN; bilirubin (total, direct, indirect):>1.5*ULN; aspartate aminotransferase(AT), alanine AT, lactate dehydrogenase, alkaline phosphatase:>3.0*ULN; blood urea nitrogen, creatinine, cholesterol (total, LDL, HDL), triglycerides, Hg A1C: >1.3*ULN; sodium: <0.95*LLN>1.05*ULN; potassium, chloride, calcium, magnesium, bicarbonate: <0.9*LLLN>1.1*ULN; prolactin: >1.1*ULN; creatine kinase: >2.0*ULN; urobilinogen: >=1; Urine-specific gravity: <1.003>1.030, pH: <4.5 >8, glucose, protein, bilirubin, nitrite, leukocyte esterase, ketones: >=1. | A1281201: Day 1 up to 1 Week after last dose of study medication (maximum up to 27 Weeks) | 
| Number of Participants With Physical Examination Abnormalities at Baseline and Week 26 | Parameters assessed for physical examination included: oral/tympanic temperature, general appearance, skin, head, ears, eyes, nose, throat, heart, lungs, breasts (if medically indicated), abdomen, external genitalia (if medically indicated), extremities, back/spinal system, lymph nodes or worsening of medical history conditions. Abnormality in physical examination was at the investigator's discretion. | Baseline (last measurement from A1281198), Week 26 of A1281201 | 
| Change From Baseline in Blood Pressure at Week 1, 2, 4, 6, 10, 14, 18, 22, 26 and Follow-up Visit | Change from baseline in sitting and standing systolic and diastolic blood pressure in millimeter of mercury (mmHg) was reported. | Baseline (last measurement from A1281198), A1281201: Week 1, 2, 4, 6, 10, 14, 18, 22, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Pulse Rate at Week 1, 2, 4, 6, 10, 14, 18, 22, 26 and Follow-up Visit | Change from baseline pulse rate in beats per minute was reported in sitting and standing positions. | Baseline (last measurement from A1281198), A1281201: Week 1, 2, 4, 6, 10, 14, 18, 22, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Height and Waist Circumference at Week 6, 26 and Follow-up Visit | Change from baseline in height and waist circumference in centimeter (cm) was reported. | Baseline (last measurement from A1281198), A1281201: Week 6, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Body Weight at Week 6, 26 and Follow-up Visit | Change from baseline in body weight in kilogram (kg) was reported. | Baseline (last measurement from A1281198), A1281201: Week 6, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Body Mass Index (BMI) at Week 6, 26 and Follow-up Visit | Change from baseline in BMI in kilogram per meter square (kg/m^2) was reported. | Baseline (last measurement from A1281198), A1281201: Week 6, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Body Mass Index (BMI) Z-score at Week 6, 26 and Follow-up Visit | BMI z-score was reported using the Children's Hospital of Philadelphia z-score calculator. Z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher BMI. | Baseline (last measurement from A1281198), A1281201: Week 6, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Heart Rate at Day 1, Week 1, 2, 4, 6, 14, 22, 26 and Follow-up Visit | Change from baseline in heart rate in beats per minute was reported. | Baseline of A1281198, Day 1 (last measurement from A1281198), A1281201: Week 1, 2, 4, 6, 14, 22, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Electrocardiogram (ECG) Parameters at Day 1, Week 1, 2, 4, 6, 14, 22, 26 and Follow-up Visit | Change from baseline in PR interval, QT interval corrected using the Bazett's correction (QTcB), QT interval corrected using the Fridericia's formula (QTcF), QT interval, RR interval, QRS duration in millisecond (msec) was reported. | Baseline of A1281198, Day 1 (last measurement from A1281198), A1281201: Week 1, 2, 4, 6, 14, 22, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Simpson-Angus Rating Scale (SARS) Total Score at Week 1, 2, 4, 6, 10, 14, 18, 22, 26 and Follow-up Visit | SARS: 10-item clinician rated instrument to assess parkinsonian symptoms and related extrapyramidal side effects. All 10 items were anchored on a 5-point scale: range 0 (absence of condition, normal) to 4 (the most extreme form of condition). Total score is sum of individual item scores, ranged from 0 (normal) to 40 (most extreme symptoms and effects); higher score indicates more affected. Rows with only non-zero data/values for change in SARS total score at specified time points, for at least 1 reporting arm, are reported below. | Baseline (last measurement from A1281198), A1281201: Week 1, 2, 4, 6, 10, 14, 18, 22, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Global Clinical Assessment of Akathisia Subscale Score of Barnes Akathisia Rating Scale (BAS) at Week 1, 2, 4, 6, 10, 14, 18, 22, 26 and Follow-up Visit | BAS: clinician rated scale to assess akathisia by determining the degree of subjective restlessness and distress associated with restlessness. Global clinical assessment of akathisia subscale score of BAS, was rated on a 6-point scale range 0 (no symptoms) to 5 (maximum severity of symptoms); higher score indicates increased severity. | Baseline (last measurement from A1281198), A1281201: Week 1, 2, 4, 6, 10, 14, 18, 22, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Movement Cluster Subscale Score of Abnormal Involuntary Movement Scale (AIMS) at Week 1, 2, 4, 6, 10, 14, 18, 22, 26 and Follow-up Visit | AIMS: clinician rated 12-item scale to document occurrences of dyskinesia in participants, specifically tardive dyskinesia. Items 1 to 10, scored as 0 (none) to 4 (severe); higher score indicates greater severity. Items 11 to 12 are questions with No or Yes response. Only the sum of the first 7 items were calculated to evaluate AIMS movement cluster subscale score, giving it a possible score range of 0 (none) to 28 (maximum severity), higher scores indicate greater severity. Rows with only non-zero data/values for change in AIMS-movement cluster subscale score at specified time points, for at least 1 reporting arm, are reported below. | Baseline (last measurement from A1281198), A1281201: Week 1, 2, 4, 6, 10, 14, 18, 22, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Number of Participants With Columbia Classification Algorithm of Suicide Assessment (C-CASA) Categorization Mapped From Columbia-Suicide Severity Rating Scale (C-SSRS) | C-SSRS: a measure used to identify and assess participants at risk for suicide. It is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors. C-SSRS items were mapped to the following C-CASA categories: completed suicide, attempted suicide (actual attempt; aborted attempt; interrupted attempt), non-suicidal self-injurious behavior, preparatory acts, suicidal ideation (wish to be dead; non-specific active suicidal thoughts; active suicidal ideation with any methods [not plan], without intent to act; active suicidal ideation with some intent to act, without specific plan; active suicidal ideation with specific plan and intent; self-injurious behavior, no suicidal intent). C-CASA categories with at least 1 participant, for specified time points, for at least 1 reporting arm are reported below. | Baseline (last measurement from A1281198), A1281201: Week 1, 2, 4, 6, 10, 14, 18, 22, 26, and Follow-up Visit (1 Week from last dose of study medication, anytime maximum up to Week 27) | 
| Change From Baseline in Children's Depression Rating Scale (CDRS-R) Total Score at Week 26 | CDRS-R: clinician-rated interview-based scale to assess 17 distinct symptom areas to derive an index of depression severity. Each symptom area was rated on a 7-point scale; range from 1 (no impairment) to 17 (maximum impairment). Total CDRS-R score was calculated as sum of responses for each 7 symptom areas. Total CDRS-R score ranged from 17 (no impairment) to 119 (maximum impairment); higher score indicated greater impairment. | Baseline (last measurement from A1281198), A1281201: Week 26 | 
| Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 1, 2, 6, 14, 22, 26 | YMRS: an 11-item scale that measured the severity of manic episodes. Four items (irritability, speech, thought content, and disruptive/ aggressive behavior) were rated on a scale from 0 (symptom absent) to 8 (symptom extremely severe). The remaining items were rated on a scale from 0 (symptom absent) to 4 (symptom extremely severe). YMRS total score was sum of score of all 11 items and ranged from 0 (no symptoms) to 60 (extreme severity of symptoms), higher score indicated higher severity of mania. | Baseline (last measurement from A1281198), A1281201: Week 1, 2, 6, 14, 22, 26 | 
| Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at Week 1, 2, 4, 6, 10, 14, 18, 22, 26 | CGI-S: 7-point clinician rated scale to assess severity of participant's current illness state. CGI-S score ranged from 1 (not ill at all) to 7 (among the most extremely ill), higher scores indicated more severity of illness. | Baseline (last measurement from A1281198), A1281201: Week 1, 2, 4, 6, 10, 14, 18, 22, 26 | 
| Change From Baseline in Children's Global Assessment Scale (CGAS) Total Score at Week 26 | CGAS: a clinician-rated global assessment item for children, based on symptoms and social functioning in home, school, and community settings. Scores ranged from 1 (extremely impaired) to 100 (doing very well), where higher levels indicate better health. | Baseline (last measurement from A1281198), A1281201: Week 26 |