High-Dose Oral Ziprasidone Versus Conventional Dosing in Schizophrenia Patients With Residual Symptoms (HDZ)
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).
|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|
- 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 ]
- 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 ]
|Study Start Date:||January 2006|
|Study Completion Date:||May 2011|
|Primary Completion Date:||May 2011 (Final data collection date for primary outcome measure)|
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.
|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|
|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|
|Principal Investigator:||Donald Goff, M.D.||Massachusetts General Hospital|