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

Study Overview
=================
Brief Summary
-----------------
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).

Official Title
-----------------
High-Dose Oral Ziprasidone Versus Conventional Dosing in Schizophrenia Patients With Residual Symptoms

Conditions
-----------------
Schizophrenia

Intervention / Treatment
-----------------
* Drug: Ziprasidone 80-160 mg/d
* Drug: Placebo
* Drug: Ziprasidone 160 mg/d


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-Dose Ziprasidone<br>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<br>* 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).<br>* Other names: Geodon;Drug: Ziprasidone 160 mg/d<br>* 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.<br>* Other names: Geodon;|
| Placebo Comparator: Placebo, Standard Treatment Ziprasidone<br>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<br>* 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.<br>Drug: Ziprasidone 160 mg/d<br>* 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.<br>* Other names: Geodon;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Events Recorded Based on Ziprasidone Side Effects Checklist During Randomized Trial | 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. | From Baseline up to Week 8 | 
| Change From Baseline in Simpson Angus Scale for Extrapyramidal Symptoms (SAS) | 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. | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| Change From Baseline in the Barnes Akathisia Scale (BAS) | 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. | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| Number of Participants With High and Low Levels in Serum Prolactin Concentration | 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. | Baseline, Week 8 | 
| Vital Signs: Systolic and Diastolic Blood Pressure Levels | 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. | Baseline, Week 1, Week 2, Week 4, Week 6, Week 8 | 
| Electrocardiogram (EKG): Number of Participants With an Increase From Baseline to Corrected QT (QTc) Interval >/= 500 Milliseconds (Msec) | 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. | 6 hours after dosing of Weeks 1, 2 and 8 | 
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score | 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. | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| Percentage of Participants With Response | 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. | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Score | 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. | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| Number of Treatment-emergent Adverse Events During Randomized Trial | 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. | From Baseline up to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Positive Subscale Score of PANSS | 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. | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| Change From Baseline in PANSS Negative Subscale Score | 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. | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| Change From Baseline in the Calgary Depression Rating Scale (CDRS) Total Score | 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. | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| Change From Baseline in Clinical Global Impression- Severity (CGI-S) Score | 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. | Baseline, Week 8 | 
| Change From Baseline in Clinical Global Impression - Improvement (CGI-I) Score | 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. | Baseline, Week 8 | 
| Change From Baseline in Global Assessment of Functioning (GAF) Score | 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. | Baseline, Week 8 | 
| Change in Schizophrenia Cognition Rating Scale (SCoRS) Score | 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. | Baseline, Week 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Schizophrenia