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High-Dose Oral Ziprasidone Versus Conventional Dosing in Participants With Residual Schizophrenia Symptoms (HDZ)

This study has been completed.
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Donald C. Goff, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT00403546
First received: November 21, 2006
Last updated: June 2, 2017
Last verified: June 2017
  Purpose

The primary aims of this study are to assess tolerability of ziprasidone dose escalation to 320 milligrams per day (mg/d) compared to continued standard treatment (placebo) as measured by the Side Effect Checklist, Simpson Angus Scale for Extrapyramidal Symptoms (SAS), Barnes Akathisia Scale (BAS), serum prolactin concentrations, vital signs, electrocardiogram (EKG) and completion rates and to assess whether ziprasidone dose escalation improves overall psychopathology compared to continued standard treatment as measured by the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score and response rates as defined by a 20% or greater reduction in PANSS total score.

The secondary aims of this study are to assess whether ziprasidone dose escalation improves psychotic symptoms compared to continued standard treatment as measured by the Positive Symptom Subscale of the PANSS, to assess whether ziprasidone dose escalation improves negative symptoms compared to standard treatment as measured by the Negative Symptom Subscale of the PANSS, to assess whether ziprasidone dose escalation improves depressive symptoms compared to continued standard treatment as measured by the Calgary Depression Rating Scale (CDRS), and to assess whether ziprasidone dose escalation improves overall functioning with the Clinical Global Impression - Severity (CGI-S), Clinical Global Impression - Improvement (CGI-I), Global Assessment of Functioning (GAF) and the Schizophrenia Cognition Rating Scale (SCoRS).


Condition Intervention Phase
Schizophrenia Drug: Ziprasidone 80-160 mg/d Drug: Placebo Drug: Ziprasidone 160 mg/d Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: High-Dose Oral Ziprasidone Versus Conventional Dosing in Schizophrenia Patients With Residual Symptoms

Resource links provided by NLM:


Further study details as provided by Donald C. Goff, MD, Massachusetts General Hospital:

Primary Outcome Measures:
  • Number of Events Recorded Based on Ziprasidone Side Effects Checklist During Randomized Trial [ Time Frame: From Baseline up to Week 8 ]
    Side effects were tracked using the Side Effect Checklist for ziprasidone, which is a well-validated 17 item scale that records the presence or absence of side effects. Total number of side effect events is reported here.

  • Change From Baseline in Simpson Angus Scale for Extrapyramidal Symptoms (SAS) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    The SAS is a 10-item testing instrument used to evaluate drug-related extrapyramidal syndromes. The following items are included in the SAS: gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella reflex, tremor, and salivation. Total score ranges from 0 to 40 with a higher score indicating increased severity. A positive change from baseline indicates a worse outcome.

  • Change From Baseline in the Barnes Akathisia Scale (BAS) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    BAS is a rating scale that is administered by physicians to assess the severity of drug-induced akathisia, which is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. The following subcategories are scored: objective akathisia, subjective awareness of restlessness and subjective distress related to restlessness and are rated on a 4-point scale from 0 - 3. In addition, the global clinical assessment of akathisia uses a 6-point scale ranging from 0 - 5. Total score ranges from 0 to 14 with a higher score indicating increased severity. A positive change from baseline indicates a worse outcome.

  • Number of Participants With High and Low Levels in Serum Prolactin Concentration [ Time Frame: Baseline, Week 8 ]
    Blood samples were taken at baseline and Week 8 to measure serum prolactin concentrations. Normal range for females (non-pregnant) is 2-29 nanograms per deciliter (ng/dL) and for males 2-18 ng/dL. Values above the normal range were reported as High and values below the normal range were reported as Low. Reported here is the number of participants with high prolactin concentration and the number of participants with low prolactin concentration.

  • Vital Signs: Systolic and Diastolic Blood Pressure Levels [ Time Frame: Baseline, Week 1, Week 2, Week 4, Week 6, Week 8 ]
    Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at regular times during the study. Normal SBP is defined as 120 millimeters of mercury (mmHg) or below and normal DBP is defined as 80 mmHg or below. Change from baseline is indicated for each time point. A positive change from baseline indicates and increase in blood pressure and a negative change from baseline indicates a decrease.

  • Electrocardiogram (EKG): Number of Participants With an Increase From Baseline to Corrected QT (QTc) Interval >/= 500 Milliseconds (Msec) [ Time Frame: 6 hours after dosing of Weeks 1, 2 and 8 ]
    QT interval is a measure of the time between the start of the Q wave and the end of the T wave as determined by electrocardiogram (EKG). The corrected QT Interval (QTc) adjusts the QT interval for heart rate. The number of participants with an increase to QTc interval >/= 500 msec was reported.

  • Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    The PANSS is a medical scale and was used for measuring symptom severity of participants with schizophrenia in this study. Total PANSS score consists of 7 items in the Negative subscale, 7 items in the Positive subscale and 16 items in the General Psychopathology scale. Total PANSS score ranges from 30 to 210. A higher score indicates a worse outcome. A negative change from baseline indicates an improvement.

  • Percentage of Participants With Response [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    Response was defined as a reduction in the PANSS total score from baseline by 20% or greater, calculated by first subtracting 30 (the PANSS minimum possible total score). Response rate is the percentage of participants with a response.

  • Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Score [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    AIMS is a rating scale measuring involuntary movements known as tardive dyskinesia, that sometimes develop as a side effect of long-term treatment with antipsychotic medications. The AIMS score was calculated as the sum of questions 1 through 7 of the AIMS instrument, which includes assessments of involuntary movements in the face, lips, jaw, tongue, upper and lower extremities, and neck/shoulders/hips. Each item is rated on a five-point scale of severity from 0-4 with 0 (none), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe). Total scores range from 0 to 28. A negative change from baseline indicates an improvement.

  • Number of Treatment-emergent Adverse Events During Randomized Trial [ Time Frame: From Baseline up to Week 8 ]
    Adverse event: any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Serious adverse event (SAE): significant hazard, contraindication, side effect, or precaution, which fulfilled any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here.


Secondary Outcome Measures:
  • Change From Baseline in Positive Subscale Score of PANSS [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    The PANSS is a medical scale and was used for measuring symptom severity of participants with schizophrenia in this study. Positive symptoms as defined by the American Psychiatric Association refer to an excess or distortion of normal functions and include the following 7 items: delusions, conceptual disorganization, hallucinations, excitement, grandiosity, suspiciousness/persecution and hostility. Score ranges from 7 to 49 with a higher score indicating a worse outcome. A negative change from baseline indicates an improvement.

  • Change From Baseline in PANSS Negative Subscale Score [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    The PANSS is a medical scale and was used for measuring symptom severity of participants with schizophrenia in this study. Negative symptoms as defined by the American Psychiatric Association represent a diminution or loss of normal functions and include the following 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation and stereotyped thinking. Score ranges from 7 to 49 with a higher score indicating a worse outcome. A negative change from baseline indicates an improvement.

  • Change From Baseline in the Calgary Depression Rating Scale (CDRS) Total Score [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    The CDRS was used to assess the level of depression in participants with schizophrenia. The questionnaire consists of 9 questions rated on a 4-point scale from 0 to 3. Total range is 0 to 27 with a higher score indicating a worse outcome. A negative change from baseline indicates an improvement.

  • Change From Baseline in Clinical Global Impression- Severity (CGI-S) Score [ Time Frame: Baseline, Week 8 ]
    CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment, relative to the clinician's past experience with subjects who have the same diagnosis. Score ranges from 1 to 7 with a higher score indicating a worse outcome. A negative change from baseline indicates an improvement.

  • Change From Baseline in Clinical Global Impression - Improvement (CGI-I) Score [ Time Frame: Baseline, Week 8 ]
    CGI-I is a 7 point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to baseline. Score ranges from 1 to 7 with a higher score indicating a worse outcome. A negative change from baseline indicates an improvement.

  • Change From Baseline in Global Assessment of Functioning (GAF) Score [ Time Frame: Baseline, Week 8 ]
    GAF is a numeric scale used to rate social, occupational, and psychological functioning of participants. Scores range from 100 (extremely high functioning) to 1 (severely impaired). A positive change from baseline indicates an improvement.

  • Change in Schizophrenia Cognition Rating Scale (SCoRS) Score [ Time Frame: Baseline, Week 8 ]
    SCoRS is a 20 item interview-based clinical assessment that evaluates cognitive deficits and the degree to which these deficits impair participants' day-to-day functioning. The following cognitive domains are assessed: attention, memory, working memory, language production, reasoning, problem solving, motor skills, and social cognition. Score ranges from 1 to 10 with a higher score indicating a greater degree of impairment. A negative change from baseline indicates an improvement.


Enrollment: 131
Actual Study Start Date: January 2006
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High-Dose Ziprasidone
Participants with schizophrenia or schizoaffective disorder who remain symptomatic despite treatment with ziprasidone 160 mg/d for at least 3 weeks will be instructed to take ziprasidone oral capsule twice daily added to their regular open-label ziprasidone dose (total of 240 mg/d). After the first week, the study drug will be increased to a total ziprasidone dose of 320 mg/d for 7 weeks.
Drug: Ziprasidone 80-160 mg/d
Participants will be instructed to take one study capsule of ziprasidone orally twice daily (80 mg/d). After the first week, the study drug will be increased to two capsules twice daily (160 mg/d).
Other Name: Geodon
Drug: Ziprasidone 160 mg/d
Participants will be taking open-label ziprasidone 80 mg orally twice daily for a total dose of 160 mg/d from at least 3 weeks before randomization to end of study 8 weeks after randomization.
Other Name: Geodon
Placebo Comparator: Placebo, Standard Treatment Ziprasidone
Participants with schizophrenia or schizoaffective disorder who remain symptomatic despite treatment with ziprasidone 160 mg/d for at least 3 weeks will be instructed to take matching placebo oral capsule twice daily added to their regular open-label ziprasidone dose of 160 mg/d. After the first week, the matching placebo will be increased to two capsules twice daily and their regular open-label ziprasidone will remain the same (160 mg/d) for 7 weeks.
Drug: Placebo
Participants will be instructed to take one study capsule of matching placebo orally twice daily. After the first week, the matching placebo will be increased to two capsules twice daily.
Drug: Ziprasidone 160 mg/d
Participants will be taking open-label ziprasidone 80 mg orally twice daily for a total dose of 160 mg/d from at least 3 weeks before randomization to end of study 8 weeks after randomization.
Other Name: Geodon

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Schizophrenia or Schizoaffective disorder, any subtype
  • Age 18-65 years
  • Treated with ziprasidone at a dose of 160 mg/d for at least 3 weeks with adequate compliance
  • Concomitant standing or other medications as needed (except other antipsychotics and those noted as contraindicated in the ziprasidone package insert) are permitted during all treatment phases if they were present at a stable dose for at least 6 weeks prior to the start of initial ziprasidone treatment
  • A score of 4 (moderate) or greater on any of the 7 items of the PANSS Positive Symptom Subscale
  • Clinical judgment by the investigator that doses higher than 160 mg/day are warranted due to suboptimal clinical outcome despite adequate treatment at that dose
  • Participant is judged capable of understanding all relevant risks and potential benefits of the study and has signed informed consent
  • Comorbid axis 1 conditions (including anxiety disorders, eating disorders, impulse control disorders) are permitted if they have been stable and have not been a primary focus of treatment over the previous 6 months

Exclusion Criteria:

  • Past or current intolerance of ziprasidone side effects
  • Presence of significant cardiac disease, including uncompensated congestive heart failure, myocardial infarction within the past 6 months or known history of congenital long QT interval syndrome
  • Corrected QT interval (QTc) greater than or equal to 500 milliseconds (msec)
  • Serum potassium and magnesium concentrations outside of normal limits.
  • Currently taking any medications which may affect cardiac conduction
  • Presence of any unstable or untreated medical disorder
  • Any history of seizures or seizure disorder other than febrile seizures of childhood
  • History of positive hepatitis B surface antigen
  • Human immunodeficiency virus (HIV) positive or has diagnosis of acquired immune deficiency syndrome (AIDS)
  • Any abnormal laboratory test that is judged to be clinically significant by the investigator
  • History of neuroleptic malignant syndrome (NMS), hypersensitivity or allergic response to antipsychotic therapy, including ziprasidone
  • History of clozapine treatment for refractory psychotic symptoms
  • Alcohol or substance dependence within the past 12 months or abuse within the past 3 months. Any subject with positive urine toxicology or alcohol use that is considered abnormal at baseline.
  • Clinically significant suicidal or homicidal behavior or attempts within past 6 months
  • Any subject judged by the investigator to present a danger to self or others.
  • Women of childbearing potential who are not using adequate contraception (oral contraceptives, barrier methods or who are clearly abstinent)
  • Pregnancy or breast-feeding
  • Any subject who is judged by the investigator to be unable or unlikely to comply with all study requirements, including adherence with prescribed medication regimen
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00403546

Locations
United States, Georgia
Medical College of Georgia
Augusta, Georgia, United States, 30912
United States, Massachusetts
Corrigan Mental Health Center
Fall River, Massachusetts, United States, 02720
United States, Michigan
Touchstone innovare
Grand Rapids, Michigan, United States, 49503
United States, New Mexico
University of New Mexico
Albuquerque, New Mexico, United States, 87131
United States, New York
SUNY Downstate Medical Center
Brooklyn, New York, United States, 11203
The Lieber Center for Schizophrenia Research - Columbia University
New York, New York, United States, 10032
Nathan Kline Institute
Orangeburg, New York, United States, 10962
United States, North Carolina
Duke University - John Umstead Hospital
Butner, North Carolina, United States, 27509
United States, Texas
The Mech Center
Plano, Texas, United States, 75024
Sponsors and Collaborators
Donald C. Goff, MD
Pfizer
Investigators
Principal Investigator: Donald Goff, M.D. Massachusetts General Hospital
  More Information

Responsible Party: Donald C. Goff, MD, Director of the Schizophrenia Clinical and Research Program, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00403546     History of Changes
Other Study ID Numbers: 2005-P-001372
Study First Received: November 21, 2006
Results First Received: April 17, 2017
Last Updated: June 2, 2017

Keywords provided by Donald C. Goff, MD, Massachusetts General Hospital:
Schizophrenia

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia Spectrum and Other Psychotic 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

ClinicalTrials.gov processed this record on June 23, 2017