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

This study has been completed.
Sponsor:
Collaborator:
Pfizer
Information provided by:
Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT00403546
First received: November 21, 2006
Last updated: July 5, 2011
Last verified: July 2011
  Purpose

The primary aims of this study are to assess tolerability of ziprasidone dose escalation to 320 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, 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 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 CGI-S, CGI-I, GAF and the Schizophrenia Cognition Rating Scale (SCoRS).


Condition Intervention Phase
Schizophrenia
Drug: Geodon
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, 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 Massachusetts General Hospital:

Primary Outcome Measures:
  • Tolerability as measured by the Simpson Angus Scale for Extrapyramidal Symptoms (SAS), the Barnes Akathisia Scale (BAS), serum prolactin concentrations, vital signs, EKG and completion rates. [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Assess improvements in psychotic and/or negative symptoms as measured by change from baseline on the Positive Symptom Subscale of the PANSS. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • Assess depressive symptoms as measured by change from baseline on the Calgary Depression Rating Scale (CDRS). [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • Assess changes in overall functioning as measured by the CGI-S, the CGI-I,the GAF, and the Schizophrenia Cognition Rating Scale (SCoRS) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: January 2006
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Geodon
    Geodon 160mg or placebo bid
    Other Name: Ziprasidone
  Hide Detailed Description

Detailed Description:

Ziprasidone is an atypical antipsychotic medication which has demonstrated efficacy comparable to or superior to conventional antipsychotics at doses ranging from 80 to 160 mg/d and is relatively free of weight-gain, extrapyramidal side effects, and prolactin elevation. Early dose finding trials predicted that a dose of 20-40 mg/d would produce optimal striatal D2 occupancy with repeated dosing. This estimate was later found to be incorrect, as clinical efficacy was not observed at doses below 80mg/d. Doses greater than 160mg/d were not systematically studied in randomized dose finding trials. The range of ziprasidone doses studies in early dose finding trials was constrained by concerns about cardiac conduction effects at higher doses. It has subsequently been shown that QTc prolongation is minimally increased with elevations in ziprasidone blood levels above those typically achieved with a dose of 160mg/day. In addition, ziprasidone 320mg/day did not produce significant QTc delay compared to ziprasidone 160mg/day in a randomized, prospective safety study. Deutchman and Deutchman described their clinical experience with high-dose ziprasidone stating that half of the patients experienced significant improvement in psychosis and affective symptoms following dose escalation. The investigators reported the high-dose ziprasidone was generally well-tolerated, with 75% reporting no side-effects and fewer than 10% reporting sedation, which was the most common complaint. One patient dropped out due to restlessness. Given that some patients may require ziprasidone doses above 160mg/day to achieve optimal D2 occupancy, the good tolerability, the absence of significant cardiac conduction effects at higher doses, and positive findings in a preliminary trial of high-dose ziprasidone, we propose to conduct a randomized, 8-week, placebo-controlled trial of dose escalation in patients who remain symptomatic after at least 3 weeks treatment with ziprasidone 160mg/day.

The study will include adult inpatients or outpatients with Schizophrenia or schizoaffective disorder who remain symptomatic despite treatment with ziprasidone 160mg/d for at least 3 weeks. The study will encourage a prospective, open-label trial of ziprasidone lasting at least 3 weeks for most subjects in order to verify treatment resistance; written informed consent is required for these subjects at the start of the open treatment period. Study-wide we expect to enroll 80 total subjects. At the MGH site we expect to enroll 8 subjects.

The proposed trial will be placebo-controlled, randomized, and double-blind. Subjects who are treatment resistant and meet entry criteria will then be randomly allocated to receive ziprasidone or placebo added-on to their open-label dose of ziprasidone for 8 weeks. Subjects will be stratified within each arm according to the duration of prior ziprasidone treatment (less than 6 weeks or 6 weeks and longer; for purposes of stratification this will be described as "brief" or "chronic" treatment respectively). All subjects will be randomly assigned to ziprasidone 40 mg capsules or matching placebo in a 1:1 ratio, stratified according to duration of prior ziprasidone treatment. Subjects will be instructed to take one study capsule twice daily (total of 80 mg/d) added to their regular open-label ziprasidone dose (total of 240 mg/d). After the first week, the study drug will be increased to two tablets twice daily (160 mg/d) for a total of 320 mg/d. Subjects assigned to placebo will remain on open-label ziprasidone 160 mg/d during the study.

Overall there are 7 study visits. On each visit, subjects will be evaluated with standard psychiatric rating scales of psychopathology, cognition, and side effects. In addition, we will measure serum levels of the medications used, fasting blood labs, drug screens, a pregnancy test, vital signs, and EKGs at multiple points during the study.

SCoRS Informants will complete the SCoRS rating scale at two time points: Baseline and Week 8.

The two primary endpoints will be the mean improvement in PANSS total score from baseline and response rate defined as a reduction in the PANSS total score from baseline by 20% or greater. Secondary endpoints will include mean improvements in the PANSS Positive and Negative Syndrome subscales, mean improvement in the Calgary Depression Rating Scale total score and change in GAF, CGI, and SCoRS scores. Tolerability will be measured by completion rates, changes in vital signs, treatment-emergent side effects, the SAS, BAS, and AIMS total scores, frequency of abnormal laboratory measures, and an increase in the QTc to 500 msec or greater.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
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 prn medications (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
  • Patient 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 syndrome.
  • QTc greater than or equal to 500 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; any subject who is HIV + or has diagnosis of AIDS. Any abnormal laboratory test that is judged to be clinically significant by the investigator.
  • History of 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
Massachusetts General Hospital
Pfizer
Investigators
Principal Investigator: Donald Goff, M.D. Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: Donald Goff, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00403546     History of Changes
Other Study ID Numbers: 2005-P-001372
Study First Received: November 21, 2006
Last Updated: July 5, 2011
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:
Schizophrenia

Additional relevant MeSH terms:
Schizophrenia
Mental Disorders
Schizophrenia and Disorders with Psychotic Features
Ziprasidone
Antipsychotic Agents
Central Nervous System Agents
Central Nervous System Depressants
Dopamine Agents
Dopamine Antagonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Agents
Serotonin Antagonists
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on October 23, 2014