Efficacy and Safety Trial of Flexible Doses of Oral Ziprasidone in Children and Adolescents With Bipolar I Disorder

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.

Time frame: Baseline, Week 4

Population: Intent-to-treat (ITT) included all randomized participants who had baseline measurements, took at least 1 dose of study medication (ziprasidone or placebo) and had at least 1 post-baseline visit.

CGI-S: 7-point clinician rated scale to assess severity of participant's current illness state; range: 1 (normal - not ill at all) to 7 (among the most extremely ill), higher scores indicated more severity of illness.

Time frame: Baseline, Week 1, 2, 3, 4

Population: ITT included all randomized participants who had baseline measurements, took at least 1 dose of study medication (ziprasidone or placebo) and had at least 1 post-baseline visit.

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.

Time frame: Baseline, Week 1, 2, 3

Population: ITT included all randomized participants who had baseline measurements, took at least 1 dose of study medication (ziprasidone or placebo) and had at least 1 post-baseline visit.

CGI-I: 7-point clinician rated scale which rates the participant's improvement or worsening from baseline, ranging from 1 (very much improved) to 7 (very much worse), higher scores indicate less improvement.

Time frame: Baseline, Week 1, 2, 3, 4

Population: ITT included all randomized participants who had baseline measurements, took at least 1 dose of study medication (ziprasidone or placebo) and had at least 1 post-baseline 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 score, giving a score range of 0 (none) to 28 (maximum severity), higher score indicates greater severity.

Time frame: Baseline, Week 1, 2, 3, 4

Population: ITT included all randomized participants who had baseline measurements, took at least 1 dose of study medication (ziprasidone or placebo) and had at least 1 post-baseline visit.

BAS: clinician rated scale to assess akathisia by determining the degree of subjective restlessness and distress associated with restlessness. First 3 items (objective, subjective, and distress related to restlessness) were rated on a 4-point scale with range 0 (no symptoms) to 3 (maximum severity of symptoms). Item 4, global clinical assessment of akathisia subscale, was rated on a 6-point scale, and ranged from 0 (no symptoms) to 5 (maximum severity of symptoms); higher score indicates increased severity.

Time frame: Baseline, Week 1, 2, 3, 4

Population: ITT included all randomized participants who had baseline measurements, took at least 1 dose of study medication (ziprasidone or placebo) and had at least 1 post-baseline visit.

Change from baseline in sitting and standing systolic blood pressure and diastolic blood pressure in millimeter of mercury (mmHg) was reported.

Time frame: Baseline, Week 1, 2, 3, 4, Early Termination Visit (anytime from Day 1 to Week 4), Follow up Visit (anytime from Day 1 up to 5 weeks after last dose of study drug = anytime from Day 1 to Week 9)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo). Here 'number analyzed' signifies number of participants evaluable for each specified row.

Change from baseline in BMI in kilogram per meter square (kg/m\^2) was reported.

Time frame: Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo). Here 'number analyzed' signifies number of participants evaluable for this outcome measure at specified time points.

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.

Time frame: Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo). Here 'number analyzed' signifies number of participants evaluable for this outcome measure at specified time points.

Change from baseline in body weight in kilogram (kg) was reported.

Time frame: Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo). Here 'number analyzed' signifies number of participants evaluable for this outcome measure at specified time points.

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 (maximum impairment). Higher scores indicated greater impairment. Total score calculated as sum of the 17 items ranged from 17 (no impairment) to 119 (maximum impairment); higher score indicated greater impairment.

Time frame: Baseline, Week 1, 2, 3, 4, Early Termination Visit (anytime from Day 1 to Week 4)

Population: ITT included all randomized participants who had baseline measurements, took at least 1 dose of study medication (ziprasidone or placebo) and had at least 1 post-baseline visit. Here 'number analyzed' signifies number of participants evaluable for this outcome measure at specified time points.

Change from baseline in height and waist circumference in centimeter (cm) was reported.

Time frame: Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo). Here 'number analyzed' signifies number of participants evaluable for each specified row.

Change from baseline pulse rate in (beats per minute) was reported in sitting and standing positions.

Time frame: Baseline, Week 1, 2, 3, 4, Early Termination Visit (anytime from Day 1 to Week 4), Follow up Visit (anytime from Day 1 up to 5 weeks after last dose of study drug = anytime from Day 1 to Week 9)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo). Here 'number analyzed' signifies number of participants evaluable for each specified row.

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 SARS score is sum of all individual item scores, and ranged from 0 (normal) to 40 (most extreme symptoms and effects); higher score indicates more affected.

Time frame: Baseline, Week 1, 2, 3, 4

Population: ITT included all randomized participants who had baseline measurements, took at least 1 dose of study medication (ziprasidone or placebo) and had at least 1 post-baseline visit.

Concomitant medications or treatments were those prescription and over-the-counter drugs and supplements or non drug treatment/procedures other than the study medication.

Time frame: Screening (2 Weeks prior to Day 1) up to 1 Week after administration of the final dose of study medication (maximum for 7 Weeks)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo).

An 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.

Time frame: Screening (2 Weeks prior to Day 1) up to maximum of 5 Weeks after administration of the final dose of study medication (maximum up to 11 weeks)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo).

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). Rows according to C-CASA categories at specified time points are reported in this outcome measure, only when there was non-zero data/values for at least 1 reporting arm.

Time frame: Screening (2 Weeks prior to Day 1), Baseline (Day 1), Week 1, 2, 3, 4, Early Termination Visit (anytime from Day 1 to Week 4), Follow up Visit (anytime from Day 1 up to 5 weeks after last dose of study drug = anytime from Day 1 to Week 9)

Population: ITT included all randomized participants who had baseline measurements, took at least 1 dose of study medication (ziprasidone or placebo) and had at least 1 post-baseline visit. Here 'number analyzed' signifies number of participants evaluable for each specified row.

Criteria: Hematology-hemoglobin(Hg),hematocrit,erythrocytes(ery)\<0.8\*LLN,ery mean corpuscular volume \<0.9\*LLN\>1.1\*ULN,platelets\<0.5\*LLN\>1.75\*ULN,leukocytes(leu)\<0.6\*LLN\>1.5\*ULN,lymphocytes(lym),lym/leu,neutrophils(neu),neu/leu\<0.8\*LLN\>1.2\*ULN,basophils (bas),bas/leu, eosinophils(eos), eos/leu, monocytes(mon),mon/leu\>1.2\*ULN; Clinical chemistry bilirubin: total, direct, indirect\>1.5\*ULN, aspartate aminotransferase,alanine aminotransferase, gamma glutamyl transferase, lactate dehydrogenase,alkaline phosphatase\>3.0\*ULN,protein,albumin\<0.8\*LLN\>1.2\*ULN,blood urea nitrogen,creatinine\>1.3\*ULN, urate\>1.2\*ULN,HDL\<0.8\*LLN;LDL\>1.2\*ULN cholesterol(CH),sodium\<0.95\*LLN\>1.05\*ULN,potassium, chloride,calcium,magnesium,bicarbonate\<0.9\*LLLN\>1.1\*ULN,phosphate,free thyroxine,thyroid stimulating hormone\<0.8\*LLN\>1.2\*ULN,prolactin\>1.1\*ULN,glucose\<0.6\*LLN\>1.5\*ULN,HgA1C,CH, triglycerides\>1.3\*ULN,creatine kinase\>2.0\*ULN; Urinalysis-specific gravity\<1.003\>1.030,pH\<4.5 \>8,urine glucose, protein, Hg, ketones:\>=1.

Time frame: Screening (2 Weeks prior to Day 1) up to 1 Week after administration of the final dose of study medication (maximum for 7 Weeks)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo). Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.

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.

Time frame: Screening (2 Weeks prior to Day 1) up to Week 4

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo).

Pre-defined categories for ECG were: heart rate intervals - QT interval corrected using the Fridericia's formula (QTCF) value greater than or equal to (\>=450) millisecond (msec), \>=460 msec, \>=480 msec, \>=500 msec, \>=30 msec increase, \>=60 msec increase, \>=75 msec increase, QT interval corrected using the Bazett's correction (QTCB) value \>=450 msec, \>=460 msec, \>=480 msec, \>=500 msec, \>=30 msec increase, \>=60 msec increase, \>=75 msec increase, PR value \>=25 percentage increase, QRS value \>=25 percentage increase, QT value \>=25 percentage increase, Respiratory rate (RR) value \>=25 percentage increase, and Heart rate (HR) value \>=25 percentage increase. Rows according to ECG pre-defined categories are reported in this outcome measure, only when there was non-zero data/values for at least 1 reporting arm.

Time frame: Screening (2 Weeks prior to Day 1) up to 1 Week after administration of the final dose of study medication (maximum for 7 Weeks)

Population: The safety analysis set included all participants who were randomized and took at least 1 dose of study medication (ziprasidone or placebo). Here ' Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.