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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02075047
Recruitment Status : Terminated (Based on recent input from FDA, the pre-specified final analysis will be performed at the current enrollment using a re-estimation of the sample size.)
First Posted : March 3, 2014
Results First Posted : April 1, 2021
Last Update Posted : April 1, 2021
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Bipolar Disorder Drug: placebo oral capsules Drug: ziprasidone oral capsules Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 171 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : May 23, 2014
Actual Primary Completion Date : April 11, 2020
Actual Study Completion Date : May 18, 2020

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Change From Baseline in Young Mania Rating Scale (YMRS) Total Score at Week 4 [ Time Frame: Baseline, 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.


Secondary Outcome Measures :
  1. Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at Weeks 1, 2, 3, and 4 [ Time Frame: Baseline, Week 1, 2, 3, 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.

  2. Change From Baseline in the Young Mania Rating Scale (YMRS) Total Score at Weeks 1, 2, and 3 [ Time Frame: Baseline, Week 1, 2, 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.

  3. Clinical Global Impression of Improvement (CGI-I) Scores at Weeks 1, 2, 3, and 4 [ Time Frame: Baseline, Week 1, 2, 3, 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.


Other Outcome Measures:
  1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ 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) ]
    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.

  2. Number of Participants With Columbia Classification Algorithm of Suicide Assessment (C-CASA) Categorization Mapped From Columbia-Suicide Severity Rating Scale (C-SSRS) [ 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) ]
    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.

  3. Number of Participants Who Took at Least 1 Concomitant Medication and Concomitant Non-Drug Treatments/Procedures [ 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) ]
    Concomitant medications or treatments were those prescription and over-the-counter drugs and supplements or non drug treatment/procedures other than the study medication.

  4. Number of Participants With Laboratory Abnormalities [ 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) ]
    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.

  5. Number of Participants With Physical Examination Abnormalities [ Time Frame: Screening (2 Weeks prior to Day 1) up to Week 4 ]
    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.

  6. Change From Baseline in Blood Pressure at Week 1, 2, 3, 4, Early Termination Visit and Follow-up Visit [ 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) ]
    Change from baseline in sitting and standing systolic blood pressure and diastolic blood pressure in millimeter of mercury (mmHg) was reported.

  7. Change From Baseline in Pulse Rate at Week 1, 2, 3, 4, Early Termination Visit and Follow-up Visit [ 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) ]
    Change from baseline pulse rate in (beats per minute) was reported in sitting and standing positions.

  8. Change From Baseline in Height and Waist Circumference at Week 4 and Early Termination Visit [ Time Frame: Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4) ]
    Change from baseline in height and waist circumference in centimeter (cm) was reported.

  9. Change From Baseline in Body Weight at Week 4 and Early Termination Visit [ Time Frame: Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4) ]
    Change from baseline in body weight in kilogram (kg) was reported.

  10. Change From Baseline in Body Mass Index (BMI) at Week 4 and Early Termination Visit [ Time Frame: Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4) ]
    Change from baseline in BMI in kilogram per meter square (kg/m^2) was reported.

  11. Change From Baseline in Body Mass Index (BMI) Z-score at Week 4 and Early Termination Visit [ Time Frame: Baseline, Week 4, Early Termination Visit (anytime from Day 1 to Week 4) ]
    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.

  12. Number of Participants With Pre-defined Categories of Electrocardiogram (ECG) Findings [ 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) ]
    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.

  13. Change From Baseline in Children's Depression Rating Scale (CDRS-R) Total Score at Weeks 1, 2, 3, and 4 and Early Termination Visit [ Time Frame: Baseline, Week 1, 2, 3, 4, Early Termination Visit (anytime from Day 1 to Week 4) ]
    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.

  14. Change From Baseline in Simpson-Angus Rating Scale (SARS) Total Score at Weeks 1, 2, 3, and 4 [ Time Frame: Baseline, Week 1, 2, 3, 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.

  15. Change From Baseline in Barnes Akathisia Rating Scale (BAS): Global Clinical Assessment of Akathisia Subscale Score at Weeks 1, 2, 3, and 4 [ Time Frame: Baseline, Week 1, 2, 3, 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.

  16. Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) - Movement Cluster Score at Weeks 1, 2, 3, and 4 [ Time Frame: Baseline, Week 1, 2, 3, 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.



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Ages Eligible for Study:   10 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02075047


Locations
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Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Statistical Analysis Plan  [PDF] July 21, 2020
Study Protocol  [PDF] February 19, 2019

Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02075047    
Other Study ID Numbers: A1281198
First Posted: March 3, 2014    Key Record Dates
Results First Posted: April 1, 2021
Last Update Posted: April 1, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
Bipolar I Disorder (current or most recent episode manic). Children and adolescents aged 10 to 17 years.
Additional relevant MeSH terms:
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Disease
Bipolar Disorder
Pathologic Processes
Bipolar and Related Disorders
Mental Disorders
Ziprasidone
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents