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

A PHASE 3, MULTICENTER, FOUR-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP EFFICACY AND SAFETY TRIAL OF FLEXIBLE DOSES OF ORAL ZIPRASIDONE IN CHILDREN AND ADOLESCENTS WITH BIPOLAR I DISORDER (CURRENT OR MOST RECENT EPISODE MANIC)

The purpose of this study is to determine if ziprasidone is safe and effective for the treatment of children and adolescents (ages 10-17) with bipolar I disorder (manic or mixed).

Study Overview

• Status: Terminated
• Conditions: Bipolar Disorder
• Intervention / Treatment: Drug: placebo oral capsules; Drug: ziprasidone oral capsules

• Study Type: Interventional
• Enrollment (Actual): 171
• Phase: Phase 3

Contacts and Locations

Study Locations

• Ukraine
  • Dnipro, Ukraine, 49027
    • Communal Non profit Enterprise "City Children Clinical Hospital #5 of Dnipro Regional Council"
  • Dnipro, Ukraine, 49101
    • Communal Nonprofit Enterprise "City Children Clinical Hospital #5 of Dnipro Regional Council
  • Odesa, Ukraine, 65006
    • Communal Nonprofit Enterprise "Odesa Regional Medical Centre of Mental Health" of Odesa
  • Vinnytsya, Ukraine, 21018
    • Municipal Institution "Vinnytsya Regional Psychoneurologycal Hospital Named After O.I. Yushenko"
• United States
  • Alabama
    • Dothan, Alabama, United States, 36303
      • Harmonex Neuroscience Research, Inc.
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Woodland International Research Group Inc.
    • Little Rock, Arkansas, United States, 72211
      • Woodland International Research Group, LLC
  • California
    • Anaheim, California, United States, 92804
      • California Pharmaceutical Research Institute
    • Orange, California, United States, 92868
      • NRC Research Institute
    • Panorama City, California, United States, 91402
      • Asclepes Research Centers
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center MIND Institute
    • Wildomar, California, United States, 92595
      • Elite Clinical Trials, Incorporated
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Health System
  • Florida
    • Boca Raton, Florida, United States, 33487
      • Da Vinci Research Institute Inc
    • Gainesville, Florida, United States, 32607
      • Sarkis Clinical Trials
    • Orange City, Florida, United States, 32763
      • Medical Research Group of Central Florida
    • Orlando, Florida, United States, 32803
      • APG Research LLC
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • Atlanta Center for Medical Research
    • Fayetteville, Georgia, United States, 30214
      • Inova Clinical Trials and Research Centre
    • Smyrna, Georgia, United States, 30082-2629
      • Attalla Consultants, LLC dba Institute for Behavioral Medicine
  • Illinois
    • Vernon Hills, Illinois, United States, 60061
      • Sleep and Behavior Medicine Institute
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Hugo W. Moser Research Institute at Kennedy Krieger Institute Clinical Trials Unit
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute Inpatient Clinic
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute Outpatient Clinic
    • Baltimore, Maryland, United States, 21205
      • Psychiatric Mental Health Program at Kennedy Krieger Institute Clinical Trials Unit
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Hospital Pediatric Clinical Research Unit
    • Baltimore, Maryland, United States, 21287
      • Charlotte R. Bloomberg Children's Center
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital Investigational Drug Services
  • New Jersey
    • Marlton, New Jersey, United States, 08053
      • Clinical Research Integrity(CRI) Lifetree, LLC
  • New York
    • Buffalo, New York, United States, 14215
      • Erie County Medical Center/State University of New York (SUNY) at Buffalo Affiliate
    • Glen Oaks, New York, United States, 11004
      • The Zucker Hillside Hospital Northwell Health
    • New York, New York, United States, 10022
      • Manhattan Behavioral Medicine
    • Rochester, New York, United States, 14618
      • Finger Lakes Clinical Research
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73116
      • Cutting Edge Research Group
    • Oklahoma City, Oklahoma, United States, 73112
      • Sooner Clinical Research
    • Oklahoma City, Oklahoma, United States, 73118
      • Paradigm Research Professionals, LLC
  • Texas
    • Houston, Texas, United States, 77054
      • UT Health Science Center at Houston (UTHSC-H)
    • Plano, Texas, United States, 75093
      • Research Across America
    • Plano, Texas, United States, 75093
      • AIM Trials
    • The Woodlands, Texas, United States, 77381
      • Family Psychiatry of The Woodlands
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Fontaine Medical Laboratories
    • Charlottesville, Virginia, United States, 22903
      • Northridge Medical Plaza
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Center for Psychopharmacology Research in Youth
    • Charlottesville, Virginia, United States, 22903
      • UVA Child & Family Psychiatry Clinic
    • Petersburg, Virginia, United States, 23805
      • Clinical Research Partners, LLC
    • Roanoke, Virginia, United States, 24014
      • Carilion Medical Center
  • Washington
    • Everett, Washington, United States, 98201
      • Eastside Therapeutic Resource dba Core Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• DSM V criteria for Bipolar I disorder (manic or mixed); age 10 - 17 years.

Exclusion Criteria:

• Imminent risk of suicide or homicide, as judged by the site investigator; any history of serious or unstable medical illness, including risk for QT prolongation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 1	Drug: placebo oral capsules; Placebo matching the oral ziprasidone capsules of 20,40, 60 and 80 mg in strength. Subjects will be dosed for 4 weeks using a flexible dosing design. Dosing is stratified based on weight, with subjects <45 kg having a target dose range of 60-80 mg/day and subjects >/= 45 kg having a target dose range of 120-180 mg/day.
Experimental: ziprasidone	Drug: ziprasidone oral capsules; Oral ziprasidone capsules of 20,40, 60 and 80 mg in strength. Subjects will be dosed for 4 weeks using a flexible dosing design. Dosing is stratified based on weight, with subjects <45 kg having a target dose range of 60-80 mg/day and subjects >/= 45 kg having a target dose range of 120-180 mg/day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 4	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, Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at Weeks 1, 2, 3, and 4	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.	Baseline, Week 1, 2, 3, 4
Change From Baseline in the Young Mania Rating Scale (YMRS) Total Score at Weeks 1, 2, and 3	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, Week 1, 2, 3
Clinical Global Impression of Improvement (CGI-I) Scores at Weeks 1, 2, 3, and 4	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.	Baseline, Week 1, 2, 3, 4

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	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)
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). 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.	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)
Number of Participants Who Took at Least 1 Concomitant Medication and Concomitant Non-Drug Treatments/Procedures	Concomitant medications or treatments were those prescription and over-the-counter drugs and supplements or non drug treatment/procedures other than the study medication.	Screening (2 Weeks prior to Day 1) up to 1 Week after administration of the final dose of study medication (maximum for 7 Weeks)
Number of Participants With Laboratory Abnormalities	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.	Screening (2 Weeks prior to Day 1) up to 1 Week after administration of the final dose of study medication (maximum for 7 Weeks)
Number of Participants With Physical Examination Abnormalities	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.	Screening (2 Weeks prior to Day 1) up to Week 4
Change From Baseline in Blood Pressure at Week 1, 2, 3, 4, Early Termination Visit and Follow-up Visit	Change from baseline in sitting and standing systolic blood pressure and diastolic blood pressure in millimeter of mercury (mmHg) was reported.	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)
Change From Baseline in Pulse Rate at Week 1, 2, 3, 4, Early Termination Visit and Follow-up Visit	Change from baseline pulse rate in (beats per minute) was reported in sitting and standing positions.	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)
Change From Baseline in Height and Waist Circumference at Week 4 and Early Termination Visit	Change from baseline in height and waist circumference in centimeter (cm) was reported.	Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4)
Change From Baseline in Body Weight at Week 4 and Early Termination Visit	Change from baseline in body weight in kilogram (kg) was reported.	Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4)
Change From Baseline in Body Mass Index (BMI) at Week 4 and Early Termination Visit	Change from baseline in BMI in kilogram per meter square (kg/m^2) was reported.	Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4)
Change From Baseline in Body Mass Index (BMI) Z-score at Week 4 and Early Termination 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, Week 4, Early Termination Visit (anytime from Day 1 to Week 4)
Number of Participants With Pre-defined Categories of Electrocardiogram (ECG) Findings	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.	Screening (2 Weeks prior to Day 1) up to 1 Week after administration of the final dose of study medication (maximum for 7 Weeks)
Change From Baseline in Children's Depression Rating Scale (CDRS-R) Total Score at Weeks 1, 2, 3, and 4 and Early Termination Visit	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.	Baseline, Week 1, 2, 3, 4, Early Termination Visit (anytime from Day 1 to Week 4)
Change From Baseline in Simpson-Angus Rating Scale (SARS) Total Score at Weeks 1, 2, 3, and 4	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.	Baseline, Week 1, 2, 3, 4
Change From Baseline in Barnes Akathisia Rating Scale (BAS): Global Clinical Assessment of Akathisia Subscale Score at Weeks 1, 2, 3, and 4	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.	Baseline, Week 1, 2, 3, 4
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) - Movement Cluster Score at Weeks 1, 2, 3, and 4	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.	Baseline, Week 1, 2, 3, 4

Collaborators and Investigators

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Publications and helpful links

General Publications

• Findling RL, Atkinson S, Bachinsky M, Raiter Y, Abreu P, Ianos C, Chappell P. Efficacy, Safety, and Tolerability of Flexibly Dosed Ziprasidone in Children and Adolescents with Mania in Bipolar I Disorder: A Randomized Placebo-Controlled Replication Study. J Child Adolesc Psychopharmacol. 2022 Apr;32(3):143-152. doi: 10.1089/cap.2021.0121. Epub 2022 Apr 7.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2014
• Primary Completion (Actual): April 11, 2020
• Study Completion (Actual): May 18, 2020

Study Registration Dates

• First Submitted: February 27, 2014
• First Submitted That Met QC Criteria: February 27, 2014
• First Posted (Estimate): March 3, 2014

Study Record Updates

• Last Update Posted (Actual): June 16, 2021
• Last Update Submitted That Met QC Criteria: June 15, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Bipolar I Disorder (current or most recent episode manic). Children and adolescents aged 10 to 17 years.
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Bipolar and Related Disorders; Disease; Bipolar Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; Ziprasidone
• Other Study ID Numbers: A1281198

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No