Bipolar Disorder, Depression, Bipolar
Conditions
Brief summary
The purpose of this study is to determine if a treatment regimen of ziprasidone plus a mood stabilizer is safe and effective in the short term treatment of Bipolar I Depression. Ziprasidone will be added to lithium, valproate or lamotrigine after the patient has been on a therapeutic dose of one of these mood stabilizers for at least 4 weeks.
Interventions
DRUGZiprasidone
Oral capsule formulation to be administered every day for duration of patient's participation in the trial - 40 mg on Day 1; 40 mg twice a day (BID) on Day 2; Flexible BID dosing of 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg or 160 mg total daily dose from Day 3 through Week 6. Dose increases of up to 40 mg/day can occur after subject has received previous lower dose for at least 1 day.
DRUGPlacebo
Matching placebo oral capsules to be administered as per the instructions for the ziprasidone arm
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for Bipolar I disorder, most recent episode depressed, with or without rapid cycling and without psychotic features. Subjects receive therapeutic dose of lithium, valproate or lamotrigine for at least 4 weeks prior to randomization.
Exclusion criteria
* Patients with ultra-fast rapid cycling (8 or more mood episodes per year) * Significant heart disease including abnormalities in the heart's rhythm (QT prolongation) * Psychotic symptoms (hallucinations and/or delusions).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | Baseline, Week 6 | MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). Change calculated as a difference between post-baseline observation and baseline MADRS score values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 | CGI-S is a single-item clinician rated scale used to assess global severity of bipolar illness based on an overall evaluation of symptoms of bipolar mania, associated behavioral symptoms, and condition of the subject. Scores range from 1 (normal, not at all ill) to 7 (among the most severely ill subjects). Higher score = more affected. Change calculated as a difference between post-baseline observation and baseline CGI-S score values. |
| Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Baseline, Week 6 | SDS is a 5-item subject rated scale to measure the extent to which work and or school, social life and or leisure activities, and home life and or family responsibilities were impaired by psychiatric illness. Items 1 to 3 rated on 11-point scale ranging 0 (not at all) to 10 (extremely affected). Total score 0 to 30; higher score indicates greater impairment; items 4 and 5 report number of days in the last month (0 to 31) subject missed work or school or was unproductive and are rated separately. Change calculated as a difference between post-baseline observation and baseline SDS score values. |
| Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5) | Baseline, Week 6 | SDS is a 5-item subject rated scale to measure the extent to which work and or school, social life and or leisure activities, and home life and or family responsibilities were impaired by psychiatric illness. Items 1 to 3 rated on 11-point scale ranging 0 (not at all) to 10 (extremely affected). Total score 0 to 30; higher score indicates greater impairment; items 4 and 5 report number of days in the last month (0 to 31) subject missed work or school or was unproductive and are rated separately. Change calculated as a difference between post-baseline observation and baseline SDS score values. |
| Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Baseline, Week 6 | Q-LES-Q is a 16-item subject rated scale to measure satisfaction with areas of daily functioning (physical health, social relationships, medication, and overall life satisfaction); rated on a 5-point Likert scale: higher scores indicate greater enjoyment and satisfaction with general life activities. Scores for items 1 to 14 are summed for a total score and converted to 0 to 100 range. Items 15 and 16 measure satisfaction with medication and overall satisfaction and are analyzed separately. Change calculated as a difference between post-baseline observation and baseline Q-LES-Q score values. |
| Change From Baseline to Week 6 in Clinical Global Impression - Severity Scale (CGI-Severity or CGI-S) | Baseline, Week 6 | CGI-S is a single-item clinician rated scale used to assess global severity of bipolar illness based on an overall evaluation of symptoms of bipolar mania, associated behavioral symptoms, and condition of the subject. Scored from 1 (normal, not at all ill) to 7 (among the most severely ill subjects). Higher score = more affected. Change calculated as a difference between post-baseline observation and baseline CGI-S score values. |
| MADRS Remission: Number of Subjects With Total MADRS Score ≤ 12 at Week 6 | Week 6 | Number of subjects with MADRS total score ≤ 12 (indicates remission). MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). |
| MADRS Response: Number of Subjects With Total MADRS Score Reduction ≥ 50 Percent From Baseline at Week 6 | Week 6 | Number of subjects with reduction of ≥50 percent (%) in MADRS total score (indicates response). MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). Reduction calculated as (\[A-B\]/B\*100): A=value at observation; B=baseline value. |
| Clinical Global Impression - Improvement Scale (CGI-Improvement or CGI-I): Number of Subjects With Response (Much Improved or Very Much Improved) at Week 6 | Baseline, Week 6 | Number of subjects with improvement defined as CGI-I response of 1 (very much improved) or 2 (much improved). CGI-I is a single-item clinician rated scale used to assess global improvement in the subject's clinical state (bipolar mania) in response to study treatment and as compared to their status at pre-treatment baseline. Scores range from 1 (very much improved) to 4 (no change) to 7 (very much worse). Higher score = more affected. |
| Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 | MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). Change calculated as a difference between post-baseline observation and baseline MADRS score values. |
| CGI-Improvement Score | Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 | CGI-I is a single-item clinician rated scale used to assess global improvement in the subject's clinical state (bipolar mania) in response to study treatment and as compared to their status at pre-treatment baseline. Scores range from 1 (very much improved) to 4 (no change) to 7 (very much worse). Higher score = more affected. Week 6 is the primary timepoint. |
| Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score | Baseline, Week 2, Week 4, Week 6 | HAM-A is a clinician rated 14-item scale that rates the intensity of psychic anxiety (items 1 to 6 and item 14) and somatic anxiety (items 7 to 13) on a 5-point severity scale; scores range from 0 (not present) to 4 (very severe); lower score indicates less affected. Change calculated as a difference between post-baseline observation and baseline HAM-A score values. Week 6 is the primary timepoint. |
| Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6 | YMRS is clinician rated 11-item scale (elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech \[rate and amount\], language-thought disorder, content, disruptive-aggressive behavior, appearance, and insight) used to assess the severity of manic symptoms and effect of treatment on mania severity. Seven items ranked on scale from 0 to 4; 4 items ranked 0 to 8. Higher scores indicate greater severity. Change calculated as a difference between post-baseline observation and baseline YMRS score values. Week 6 is the primary timepoint. |
| Change From Baseline in Global Assessment of Functioning (GAF) Scale at Week 6 | Baseline, Week 6 | GAF is a clinician rated scale to measure the severity of illness-related impairment in psychological, social, and occupational functioning using a 100-point scale (single score of 1 to 100) with 100 indicating a superior level of function. Change calculated as a difference between post-baseline observation and baseline GAF score values. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Baseline, Week 2, Week 4, Week 6 | AIMS is a clinician rated 12-item scale to rate 7 body areas and global judgments on the severity of abnormal movements, incapacitation and subject's awareness of abnormal movements. Items 1 to 10 scored 0 (none) to 4 (severe); items 11 to 14 are No or Yes response to dental status and sleep movements and are assessed separately. AIMS total score is sum of first 7 items. Change calculated as a difference between post-baseline observation and baseline AIMS score values. |
| Change From Baseline in Barnes Akathisia Rating Scale (BARS or BAS) | Baseline, Week 2, Week 4, Week 6 | BARS is a clinician rated scale to evaluate akathisia associated with use of antipsychotic medications: objective motor restlessness, range 0 to 3; subjective complaints of restlessness and associated distress, range 0 to 3; global clinical assessment of akathisia, range 0 to 5. Higher scores indicate more affected. Change calculated as a difference between post-baseline observation and baseline BARS score values. |
| Change From Baseline in Simpson Angus Scale (SAS) Score | Baseline, Week 2, Week 4, Week 6 | SAS is a clinician rated 10-item scale to measure extrapyramidal side effects (Parkinsonism or Parkinsonian side effects induced with antipsychotics); rated on a 5-point scale with range 0 (absence of condition) to 4 (presence of condition in extreme form). Global score is sum of all scores divided by the total number of items. Change calculated as a difference between post-baseline observation and baseline SAS score values. |
Countries
Australia, India, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ziprasidone Day 1: single dose of 40 milligrams (mg) by mouth (PO); Day 2: 40 mg po twice a day (BID); Day 3 through Week 6: flexible BID dosing titrated to a total daily dose of 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg as adjunctive therapy with a mood stabilizer (lithium, valproate, or lamotrigine). | 147 |
| Placebo Day 1: single dose of 40 milligrams (mg) by mouth (PO); Day 2: 40 mg po twice a day (BID); Day 3 through Week 6: flexible BID dosing titrated to a total daily dose of 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg as adjunctive therapy with a mood stabilizer (lithium, valproate, or lamotrigine). | 147 |
| Total | 294 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 25 | 14 |
| Overall Study | Laboratory abnormality | 1 | 2 |
| Overall Study | Lack of Efficacy | 4 | 8 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Non-compliance with medication | 2 | 0 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Protocol required discontinuation | 6 | 6 |
| Overall Study | Protocol Violation | 11 | 7 |
| Overall Study | Randomized; not treated with study drug | 1 | 3 |
| Overall Study | Unable to comply with protocol schedule | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | Ziprasidone | Placebo | Total |
|---|---|---|---|
| Age, Customized >65 years | 0 participants | 1 participants | 1 participants |
| Age, Customized Between 18 and 65 years | 147 participants | 146 participants | 293 participants |
| Sex: Female, Male Female | 89 Participants | 91 Participants | 180 Participants |
| Sex: Female, Male Male | 58 Participants | 56 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 147 | 57 / 147 |
| serious Total, serious adverse events | 1 / 147 | 6 / 147 |
Outcome results
Primary
Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). Change calculated as a difference between post-baseline observation and baseline MADRS score values.
Time frame: Baseline, Week 6
Population: Intent to Treat analysis set (ITT): all randomized subjects who received at least 1 dose of double-blind treatment and had at least 1 post-baseline primary efficacy evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone | Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -14.7 scores on scale | Standard Deviation 10.7 |
| Placebo | Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -13.2 scores on scale | Standard Deviation 10.4 |
Comparison: N=141 per arm (282 total) needed for 85% power for 2-sided alpha=0.05 based on true mean difference=4.0 and standard deviation (SD)=11.0 for primary endpoint. Interim Analysis (IA) planned when 60% of subjects had completed study or discontinued prematurely to assess efficacy (nominal 2-sided p-value less than or equal to \[≤\] 0.0076) or futility (nominal 2-sided p-value greater than or equal to \[≥\] 0.5099).p-value: 0.792195% CI: [-3.07, 2.34]ANCOVA Mixed-effects repeated-measures
Secondary
CGI-Improvement Score
CGI-I is a single-item clinician rated scale used to assess global improvement in the subject's clinical state (bipolar mania) in response to study treatment and as compared to their status at pre-treatment baseline. Scores range from 1 (very much improved) to 4 (no change) to 7 (very much worse). Higher score = more affected. Week 6 is the primary timepoint.
Time frame: Week 1, Week 2, Week 3, Week 4, Week 5, Week 6
Population: ITT; LOCF; (n)=number of subjects with analyzable data at baseline and post-baseline observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | CGI-Improvement Score | Week 4 (n=106, 122) | 2.6 scores on scale | Standard Deviation 1.2 |
| Ziprasidone | CGI-Improvement Score | Week 2 (n=120, 138) | 2.9 scores on scale | Standard Deviation 1.1 |
| Ziprasidone | CGI-Improvement Score | Week 5 (n=103, 112) | 2.5 scores on scale | Standard Deviation 1.2 |
| Ziprasidone | CGI-Improvement Score | Week 1 (n=142, 141) | 3.2 scores on scale | Standard Deviation 0.9 |
| Ziprasidone | CGI-Improvement Score | Week 6 (n=92, 108) | 2.4 scores on scale | Standard Deviation 1.2 |
| Ziprasidone | CGI-Improvement Score | Week 3 (n=115, 130) | 2.7 scores on scale | Standard Deviation 1 |
| Placebo | CGI-Improvement Score | Week 6 (n=92, 108) | 2.4 scores on scale | Standard Deviation 1.1 |
| Placebo | CGI-Improvement Score | Week 1 (n=142, 141) | 3.4 scores on scale | Standard Deviation 0.8 |
| Placebo | CGI-Improvement Score | Week 2 (n=120, 138) | 3.1 scores on scale | Standard Deviation 1 |
| Placebo | CGI-Improvement Score | Week 4 (n=106, 122) | 2.8 scores on scale | Standard Deviation 1.2 |
| Placebo | CGI-Improvement Score | Week 5 (n=103, 112) | 2.6 scores on scale | Standard Deviation 1.1 |
| Placebo | CGI-Improvement Score | Week 3 (n=115, 130) | 2.9 scores on scale | Standard Deviation 1 |
Comparison: Week 1; LOCF; Analysis of variance model with treatment, country, type of mood stabilizer as fixed effects.p-value: 0.039295% CI: [-0.43, -0.01]ANOVA
Comparison: Week 2; LOCF; Analysis of variance model with treatment, country, type of mood stabilizer as fixed effects.p-value: 0.280395% CI: [-0.38, 0.11]ANOVA
Comparison: Week 3; LOCF; Analysis of variance model with treatment, country, type of mood stabilizer as fixed effects.p-value: 0.983595% CI: [-0.26, 0.26]ANOVA
Comparison: Week 4; LOCF; Analysis of variance model with treatment, country, type of mood stabilizer as fixed effects.p-value: 0.706295% CI: [-0.34, 0.23]ANOVA
Comparison: Week 5; LOCF; Analysis of variance model with treatment, country, type of mood stabilizer as fixed effects.p-value: 0.951895% CI: [-0.31, 0.29]ANOVA
Comparison: Week 6; LOCFp-value: 0.475795% CI: [-0.2, 0.42]ANOVA
Secondary
Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6)
CGI-S is a single-item clinician rated scale used to assess global severity of bipolar illness based on an overall evaluation of symptoms of bipolar mania, associated behavioral symptoms, and condition of the subject. Scores range from 1 (normal, not at all ill) to 7 (among the most severely ill subjects). Higher score = more affected. Change calculated as a difference between post-baseline observation and baseline CGI-S score values.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5
Population: ITT; LOCF; (n)=number of subjects with analyzable data: baseline and post-baseline observation for ziprasidone, placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 2 (n=120, 139) | -0.9 scores on scale | Standard Deviation 1.1 |
| Ziprasidone | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 4 (n=106, 122) | -1.1 scores on scale | Standard Deviation 1.1 |
| Ziprasidone | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 3 (n=115, 130) | -0.9 scores on scale | Standard Deviation 1 |
| Ziprasidone | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 5 (n=103, 112) | -1.3 scores on scale | Standard Deviation 1.2 |
| Ziprasidone | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 1 (n=142, 141) | -0.5 scores on scale | Standard Deviation 0.8 |
| Placebo | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 5 (n=103, 112) | -1.3 scores on scale | Standard Deviation 1.2 |
| Placebo | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 1 (n=142, 141) | -0.4 scores on scale | Standard Deviation 0.8 |
| Placebo | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 2 (n=120, 139) | -0.7 scores on scale | Standard Deviation 0.9 |
| Placebo | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 3 (n=115, 130) | -0.9 scores on scale | Standard Deviation 1 |
| Placebo | Change From Baseline in CGI-Severity Score (Post-baseline Excluding Week 6) | Week 4 (n=106, 122) | -1.1 scores on scale | Standard Deviation 1.1 |
Comparison: Week 1; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.177195% CI: [-0.29, 0.05]ANCOVA
Comparison: Week 2; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.176595% CI: [-0.37, 0.07]ANCOVA
Comparison: Week 3; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.676595% CI: [-0.27, 0.18]ANCOVA
Comparison: Week 4; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.97795% CI: [-0.24, 0.25]ANCOVA
Comparison: Week 5; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.790795% CI: [-0.3, 0.23]ANCOVA
Secondary
Change From Baseline in Global Assessment of Functioning (GAF) Scale at Week 6
GAF is a clinician rated scale to measure the severity of illness-related impairment in psychological, social, and occupational functioning using a 100-point scale (single score of 1 to 100) with 100 indicating a superior level of function. Change calculated as a difference between post-baseline observation and baseline GAF score values.
Time frame: Baseline, Week 6
Population: ITT; observed cases; Early Termination (ET) visits re-slotted to regular weekly visits according to duration since first dosing date; ET Visit only includes observations from visits that did not meet windowing criteria; (n)=number of subjects with analyzable data at baseline and post-baseline observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in Global Assessment of Functioning (GAF) Scale at Week 6 | Week 6 (n=100, 110) | 14.7 scores on scale | Standard Deviation 13.8 |
| Ziprasidone | Change From Baseline in Global Assessment of Functioning (GAF) Scale at Week 6 | ET (n=34, 27) | 0.0 scores on scale | Standard Deviation 7.1 |
| Placebo | Change From Baseline in Global Assessment of Functioning (GAF) Scale at Week 6 | Week 6 (n=100, 110) | 11.2 scores on scale | Standard Deviation 12.3 |
| Placebo | Change From Baseline in Global Assessment of Functioning (GAF) Scale at Week 6 | ET (n=34, 27) | 2.8 scores on scale | Standard Deviation 9.1 |
Comparison: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.010895% CI: [0.99, 7.5]ANCOVA
Secondary
Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score
HAM-A is a clinician rated 14-item scale that rates the intensity of psychic anxiety (items 1 to 6 and item 14) and somatic anxiety (items 7 to 13) on a 5-point severity scale; scores range from 0 (not present) to 4 (very severe); lower score indicates less affected. Change calculated as a difference between post-baseline observation and baseline HAM-A score values. Week 6 is the primary timepoint.
Time frame: Baseline, Week 2, Week 4, Week 6
Population: ITT; LOCF; (n)=number of subjects with analyzable data at baseline and post-baseline observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score | Week 2 (n=136, 141) | -5.6 scores on scale | Standard Deviation 6.8 |
| Ziprasidone | Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score | Week 4 (n=111, 127) | -7.1 scores on scale | Standard Deviation 7.2 |
| Ziprasidone | Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score | Week 6 (n=100, 111) | -8.5 scores on scale | Standard Deviation 7.9 |
| Placebo | Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score | Week 2 (n=136, 141) | -5.9 scores on scale | Standard Deviation 6.7 |
| Placebo | Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score | Week 4 (n=111, 127) | -7.4 scores on scale | Standard Deviation 7.6 |
| Placebo | Change From Baseline in Hamilton Anxiety Scale (HAM-A) Total Score | Week 6 (n=100, 111) | -8.6 scores on scale | Standard Deviation 7.5 |
Comparison: Week 2; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.636295% CI: [-1.12, 1.82]ANCOVA
Comparison: Week 4; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.456595% CI: [-0.98, 2.17]ANCOVA
Comparison: Week 6; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.47795% CI: [-1.08, 2.3]ANCOVA
Secondary
Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6)
MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). Change calculated as a difference between post-baseline observation and baseline MADRS score values.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5
Population: ITT; LOCF; (n)=number of subjects with analyzable data: baseline and post-baseline observation for ziprasidone, placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 2 (n=121, 139) | -11.7 scores on scale | Standard Deviation 8.9 |
| Ziprasidone | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 4 (n=106, 122) | -14.1 scores on scale | Standard Deviation 9.6 |
| Ziprasidone | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 3 (n=115, 130) | -13.0 scores on scale | Standard Deviation 9.5 |
| Ziprasidone | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 5 (n=103, 112) | -14.9 scores on scale | Standard Deviation 9.4 |
| Ziprasidone | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 1 (n=142, 141) | -8.1 scores on scale | Standard Deviation 7.9 |
| Placebo | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 5 (n=103, 112) | -13.3 scores on scale | Standard Deviation 10.1 |
| Placebo | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 1 (n=142, 141) | -6.1 scores on scale | Standard Deviation 7.3 |
| Placebo | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 2 (n=121, 139) | -9.0 scores on scale | Standard Deviation 8.6 |
| Placebo | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 3 (n=115, 130) | -11.0 scores on scale | Standard Deviation 9.2 |
| Placebo | Change From Baseline in MADRS Total Score (Post-baseline Excluding Week 6) | Week 4 (n=106, 122) | -11.8 scores on scale | Standard Deviation 9.5 |
Comparison: Week 1; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.059495% CI: [-3.42, 0.07]ANCOVA
Comparison: Week 2; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.22395% CI: [-3.27, 0.77]ANCOVA
Comparison: Week 3; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.697195% CI: [-2.57, 1.72]ANCOVA
Comparison: Week 4; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.548595% CI: [-2.89, 1.54]ANCOVA
Comparison: Week 5; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.832295% CI: [-2.6, 2.1]ANCOVA
Secondary
Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6
Q-LES-Q is a 16-item subject rated scale to measure satisfaction with areas of daily functioning (physical health, social relationships, medication, and overall life satisfaction); rated on a 5-point Likert scale: higher scores indicate greater enjoyment and satisfaction with general life activities. Scores for items 1 to 14 are summed for a total score and converted to 0 to 100 range. Items 15 and 16 measure satisfaction with medication and overall satisfaction and are analyzed separately. Change calculated as a difference between post-baseline observation and baseline Q-LES-Q score values.
Time frame: Baseline, Week 6
Population: ITT; ET visits re-slotted to regular weekly visits according to duration since first dosing date; ET Visit only includes observations from visits that did not meet windowing criteria; (n)=number of subjects with analyzable data at baseline and post-baseline observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Total Q-LES-Q: Week 6 (n=82, 94) | 15.2 scores on scale | Standard Deviation 19 |
| Ziprasidone | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Total Q-LES-Q: ET (n=27, 17) | -0.1 scores on scale | Standard Deviation 19.7 |
| Ziprasidone | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Medications: Week 6 (n=91, 93) | 0.4 scores on scale | Standard Deviation 1.2 |
| Ziprasidone | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Medications: ET (n=27, 20) | -0.3 scores on scale | Standard Deviation 1.2 |
| Ziprasidone | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Overall life satisfaction: Week 6 (n=94, 103) | 0.8 scores on scale | Standard Deviation 1.1 |
| Ziprasidone | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Overall life satisfaction: ET (n=31, 23) | 0.1 scores on scale | Standard Deviation 1.3 |
| Placebo | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Overall life satisfaction: Week 6 (n=94, 103) | 0.5 scores on scale | Standard Deviation 1.1 |
| Placebo | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Total Q-LES-Q: Week 6 (n=82, 94) | 11.6 scores on scale | Standard Deviation 17.3 |
| Placebo | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Medications: ET (n=27, 20) | -0.4 scores on scale | Standard Deviation 0.8 |
| Placebo | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Total Q-LES-Q: ET (n=27, 17) | 1.6 scores on scale | Standard Deviation 14.5 |
| Placebo | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Overall life satisfaction: ET (n=31, 23) | 0.0 scores on scale | Standard Deviation 0.9 |
| Placebo | Change From Baseline in Quality of Life, Enjoyment, and Satisfaction Scale (Q-LES-Q) Scores at Week 6 | Medications: Week 6 (n=91, 93) | 0.3 scores on scale | Standard Deviation 1.1 |
Comparison: Total Q-LES-Q: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.551995% CI: [-3.5, 6.53]ANCOVA
Comparison: Medications: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.523895% CI: [-0.35, 0.18]ANCOVA
Comparison: Overall life satisfaction: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.53695% CI: [-0.19, 0.36]ANCOVA
Secondary
Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3)
SDS is a 5-item subject rated scale to measure the extent to which work and or school, social life and or leisure activities, and home life and or family responsibilities were impaired by psychiatric illness. Items 1 to 3 rated on 11-point scale ranging 0 (not at all) to 10 (extremely affected). Total score 0 to 30; higher score indicates greater impairment; items 4 and 5 report number of days in the last month (0 to 31) subject missed work or school or was unproductive and are rated separately. Change calculated as a difference between post-baseline observation and baseline SDS score values.
Time frame: Baseline, Week 6
Population: ITT; ET visits re-slotted to regular weekly visits according to duration since first dosing date; ET Visit only includes observations from visits that did not meet windowing criteria; (n)=number of subjects with analyzable data at baseline and post-baseline observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Total SDS: Week 6 (n=58, 63) | -8.5 scores on scale | Standard Deviation 9.2 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Total SDS: ET (n=19, 14) | 0.2 scores on scale | Standard Deviation 6.8 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Work/School: Week 6 (n=58, 64) | -2.1 scores on scale | Standard Deviation 3.5 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Work/School: ET (n=19, 14) | 0.4 scores on scale | Standard Deviation 3 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Social life: Week 6 (n=94, 102) | -2.5 scores on scale | Standard Deviation 3.3 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Social life: ET (n=31, 23) | -0.5 scores on scale | Standard Deviation 2.9 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Family/Home: Week 6 (n=94, 102) | -2.6 scores on scale | Standard Deviation 3.2 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Family/Home: ET (n=31, 23) | 0.2 scores on scale | Standard Deviation 2.3 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Family/Home: ET (n=31, 23) | -0.6 scores on scale | Standard Deviation 3.2 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Total SDS: Week 6 (n=58, 63) | -3.7 scores on scale | Standard Deviation 8.2 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Social life: Week 6 (n=94, 102) | -1.7 scores on scale | Standard Deviation 3.2 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Total SDS: ET (n=19, 14) | -1.4 scores on scale | Standard Deviation 6.7 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Family/Home: Week 6 (n=94, 102) | -1.7 scores on scale | Standard Deviation 3.3 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Work/School: Week 6 (n=58, 64) | -1.6 scores on scale | Standard Deviation 2.9 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Social life: ET (n=31, 23) | 0.1 scores on scale | Standard Deviation 3.1 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 1 Through 3) | Work/School: ET (n=19, 14) | -0.1 scores on scale | Standard Deviation 2.7 |
Comparison: Total SDS: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.00195% CI: [-7.24, -1.87]ANCOVA
Secondary
Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5)
SDS is a 5-item subject rated scale to measure the extent to which work and or school, social life and or leisure activities, and home life and or family responsibilities were impaired by psychiatric illness. Items 1 to 3 rated on 11-point scale ranging 0 (not at all) to 10 (extremely affected). Total score 0 to 30; higher score indicates greater impairment; items 4 and 5 report number of days in the last month (0 to 31) subject missed work or school or was unproductive and are rated separately. Change calculated as a difference between post-baseline observation and baseline SDS score values.
Time frame: Baseline, Week 6
Population: ITT; ET visits re-slotted to regular weekly visits according to duration since first dosing date; ET Visit only includes observations from visits that did not meet windowing criteria; (n)=number of subjects with analyzable data at baseline and post-baseline observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5) | Days lost: Week 6 (n=85, 93) | -1.2 days | Standard Deviation 2.5 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5) | Days lost: ET (n=29, 21) | 0.5 days | Standard Deviation 2.7 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5) | Days unproductive: Week 6 (n=87, 89) | -1.6 days | Standard Deviation 2.8 |
| Ziprasidone | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5) | Days unproductive: ET (n=29, 21) | -0.2 days | Standard Deviation 2.5 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5) | Days unproductive: ET (n=29, 21) | -0.1 days | Standard Deviation 3.7 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5) | Days lost: Week 6 (n=85, 93) | -0.7 days | Standard Deviation 2.3 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5) | Days unproductive: Week 6 (n=87, 89) | -1.3 days | Standard Deviation 2.9 |
| Placebo | Change From Baseline in Sheehan Disability Scale (SDS) at Week 6 (Items 4 and 5) | Days lost: ET (n=29, 21) | 0.0 days | Standard Deviation 2.2 |
Comparison: Days Lost: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.12395% CI: [-1, 0.12]ANCOVA
Comparison: Days Unproductive: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.623295% CI: [-0.84, 0.5]ANCOVA
Secondary
Change From Baseline in Young Mania Rating Scale (YMRS) Total Score
YMRS is clinician rated 11-item scale (elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech \[rate and amount\], language-thought disorder, content, disruptive-aggressive behavior, appearance, and insight) used to assess the severity of manic symptoms and effect of treatment on mania severity. Seven items ranked on scale from 0 to 4; 4 items ranked 0 to 8. Higher scores indicate greater severity. Change calculated as a difference between post-baseline observation and baseline YMRS score values. Week 6 is the primary timepoint.
Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6
Population: ITT; LOCF; (n)=number of subjects with analyzable data at baseline and post-baseline observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 1 (n=142, 141) | 0.7 scores on scale | Standard Deviation 4.4 |
| Ziprasidone | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 2 (n=121, 139) | 0.5 scores on scale | Standard Deviation 4.5 |
| Ziprasidone | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 3 (n=115, 130) | -0.0 scores on scale | Standard Deviation 4.5 |
| Ziprasidone | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 4 (n=106, 122) | -0.9 scores on scale | Standard Deviation 4.1 |
| Ziprasidone | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 5 (n=103, 112) | -0.9 scores on scale | Standard Deviation 3.9 |
| Ziprasidone | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 6 (n=92, 108) | -1.0 scores on scale | Standard Deviation 4.8 |
| Placebo | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 5 (n=103, 112) | -1.3 scores on scale | Standard Deviation 4.1 |
| Placebo | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 1 (n=142, 141) | -0.2 scores on scale | Standard Deviation 3.5 |
| Placebo | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 4 (n=106, 122) | -1.1 scores on scale | Standard Deviation 4.2 |
| Placebo | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 2 (n=121, 139) | -0.2 scores on scale | Standard Deviation 4.3 |
| Placebo | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 6 (n=92, 108) | -0.9 scores on scale | Standard Deviation 4.6 |
| Placebo | Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | Week 3 (n=115, 130) | -0.2 scores on scale | Standard Deviation 4.9 |
Comparison: Week 1; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.127795% CI: [-0.2, 1.6]ANCOVA
Comparison: Week 2; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.234595% CI: [-0.41, 1.68]ANCOVA
Comparison: Week 3; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.833795% CI: [-1.05, 1.3]ANCOVA
Comparison: Week 4; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.464695% CI: [-0.73, 1.59]ANCOVA
Comparison: Week 5; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.399395% CI: [-0.67, 1.67]ANCOVA
Comparison: Week 6; LOCF; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.764795% CI: [-1.08, 1.46]ANCOVA
Secondary
Change From Baseline to Week 6 in Clinical Global Impression - Severity Scale (CGI-Severity or CGI-S)
CGI-S is a single-item clinician rated scale used to assess global severity of bipolar illness based on an overall evaluation of symptoms of bipolar mania, associated behavioral symptoms, and condition of the subject. Scored from 1 (normal, not at all ill) to 7 (among the most severely ill subjects). Higher score = more affected. Change calculated as a difference between post-baseline observation and baseline CGI-S score values.
Time frame: Baseline, Week 6
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ziprasidone | Change From Baseline to Week 6 in Clinical Global Impression - Severity Scale (CGI-Severity or CGI-S) | -1.5 scores on scale | Standard Deviation 1.3 |
| Placebo | Change From Baseline to Week 6 in Clinical Global Impression - Severity Scale (CGI-Severity or CGI-S) | -1.5 scores on scale | Standard Deviation 1.2 |
Comparison: Week 6; MMRM analysis of covariance model with fixed categorical effects of treatment, country, type of mood stabilizer, visit, treatment-by-visit interaction, fixed continuous effect of baseline value and subject as random effect.p-value: 0.722395% CI: [-0.25, 0.36]ANCOVA Mixed-effects repeated-measures
Secondary
Clinical Global Impression - Improvement Scale (CGI-Improvement or CGI-I): Number of Subjects With Response (Much Improved or Very Much Improved) at Week 6
Number of subjects with improvement defined as CGI-I response of 1 (very much improved) or 2 (much improved). CGI-I is a single-item clinician rated scale used to assess global improvement in the subject's clinical state (bipolar mania) in response to study treatment and as compared to their status at pre-treatment baseline. Scores range from 1 (very much improved) to 4 (no change) to 7 (very much worse). Higher score = more affected.
Time frame: Baseline, Week 6
Population: ITT; LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ziprasidone | Clinical Global Impression - Improvement Scale (CGI-Improvement or CGI-I): Number of Subjects With Response (Much Improved or Very Much Improved) at Week 6 | 66 participants |
| Placebo | Clinical Global Impression - Improvement Scale (CGI-Improvement or CGI-I): Number of Subjects With Response (Much Improved or Very Much Improved) at Week 6 | 69 participants |
Comparison: Week 6; LOCF; Logistic regression model with treatment, country, and type of mood stabilizer.p-value: 0.792495% CI: [0.59, 1.5]Regression, Logistic
Secondary
MADRS Remission: Number of Subjects With Total MADRS Score ≤ 12 at Week 6
Number of subjects with MADRS total score ≤ 12 (indicates remission). MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms).
Time frame: Week 6
Population: ITT; Last observation carried forward (LOCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ziprasidone | MADRS Remission: Number of Subjects With Total MADRS Score ≤ 12 at Week 6 | 48 participants |
| Placebo | MADRS Remission: Number of Subjects With Total MADRS Score ≤ 12 at Week 6 | 54 participants |
Comparison: Week 6; LOCF; Logistic regression model with treatment, country, and type of mood stabilizer.p-value: 0.502995% CI: [0.52, 1.38]Regression, Logistic
Secondary
MADRS Response: Number of Subjects With Total MADRS Score Reduction ≥ 50 Percent From Baseline at Week 6
Number of subjects with reduction of ≥50 percent (%) in MADRS total score (indicates response). MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts); rated on a 7-point Likert scale 0 (normal) to 6 (most abnormal); total score 0 to 44 (higher score indicates greater severity of symptoms). Reduction calculated as (\[A-B\]/B\*100): A=value at observation; B=baseline value.
Time frame: Week 6
Population: ITT; LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ziprasidone | MADRS Response: Number of Subjects With Total MADRS Score Reduction ≥ 50 Percent From Baseline at Week 6 | 62 participants |
| Placebo | MADRS Response: Number of Subjects With Total MADRS Score Reduction ≥ 50 Percent From Baseline at Week 6 | 65 participants |
Comparison: Week 6; LOCF; Logistic regression model with treatment, country, and type of mood stabilizer.p-value: 0.826695% CI: [0.59, 1.52]Regression, Logistic
Other Pre-specified
Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores
AIMS is a clinician rated 12-item scale to rate 7 body areas and global judgments on the severity of abnormal movements, incapacitation and subject's awareness of abnormal movements. Items 1 to 10 scored 0 (none) to 4 (severe); items 11 to 14 are No or Yes response to dental status and sleep movements and are assessed separately. AIMS total score is sum of first 7 items. Change calculated as a difference between post-baseline observation and baseline AIMS score values.
Time frame: Baseline, Week 2, Week 4, Week 6
Population: ITT; (n)=number of subjects with analyzable data at baseline and post-baseline observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Total score: Week 4 (n=111, 127) | -0.0 scores on scale | Standard Deviation 0.5 |
| Ziprasidone | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Global severity score: Week 6 (n=100, 111) | 0.0 scores on scale | Standard Deviation 0.3 |
| Ziprasidone | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Global severity score: Week 2 (n=136, 142) | 0.0 scores on scale | Standard Deviation 0.4 |
| Ziprasidone | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Incapacitation score: Week 2 (n=136, 142) | 0.0 scores on scale | Standard Deviation 0.2 |
| Ziprasidone | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Total score: Week 6 (n=100, 111) | -0.0 scores on scale | Standard Deviation 0.6 |
| Ziprasidone | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Incapacitation score: Week 4 (n=111, 127) | 0.0 scores on scale | Standard Deviation 0.1 |
| Ziprasidone | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Global severity score: Week 4 (n=111, 127) | 0.0 scores on scale | Standard Deviation 0.3 |
| Ziprasidone | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Incapacitation score: Week 6 (n=100, 111) | 0.0 scores on scale | Standard Deviation 0.1 |
| Ziprasidone | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Total score: Week 2 (n=136, 142) | 0.1 scores on scale | Standard Deviation 0.7 |
| Placebo | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Incapacitation score: Week 6 (n=100, 111) | 0.0 scores on scale | Standard Deviation 0.2 |
| Placebo | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Total score: Week 2 (n=136, 142) | -0.1 scores on scale | Standard Deviation 0.4 |
| Placebo | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Total score: Week 4 (n=111, 127) | -0.0 scores on scale | Standard Deviation 0.5 |
| Placebo | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Total score: Week 6 (n=100, 111) | -0.0 scores on scale | Standard Deviation 0.4 |
| Placebo | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Global severity score: Week 2 (n=136, 142) | -0.0 scores on scale | Standard Deviation 0.2 |
| Placebo | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Global severity score: Week 4 (n=111, 127) | 0.0 scores on scale | Standard Deviation 0.2 |
| Placebo | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Global severity score: Week 6 (n=100, 111) | 0.0 scores on scale | Standard Deviation 0.1 |
| Placebo | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Incapacitation score: Week 2 (n=136, 142) | -0.0 scores on scale | Standard Deviation 0.1 |
| Placebo | Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Scores | Incapacitation score: Week 4 (n=111, 127) | -0.0 scores on scale | Standard Deviation 0.2 |
Comparison: Total score: Week 2; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.027195% CI: [0.01, 0.21]ANCOVA
Comparison: Total score: Week 4; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.746295% CI: [-0.07, 0.05]ANCOVA
Comparison: Total score: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.957495% CI: [-0.08, 0.08]ANCOVA
Comparison: Global severity score: Week 2; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.084495% CI: [-0.01, 0.1]ANCOVA
Comparison: Global severity score: Week 4; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.577995% CI: [-0.04, 0.06]ANCOVA
Comparison: Global severity score: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.745595% CI: [-0.05, 0.06]ANCOVA
Comparison: Incapacitation score: Week 2; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.327895% CI: [-0.02, 0.05]ANCOVA
Comparison: Incapacitation score: Week 4; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.909795% CI: [-0.03, 0.03]ANCOVA
Comparison: Incapacitation score: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.986495% CI: [-0.04, 0.04]ANCOVA
Other Pre-specified
Change From Baseline in Barnes Akathisia Rating Scale (BARS or BAS)
BARS is a clinician rated scale to evaluate akathisia associated with use of antipsychotic medications: objective motor restlessness, range 0 to 3; subjective complaints of restlessness and associated distress, range 0 to 3; global clinical assessment of akathisia, range 0 to 5. Higher scores indicate more affected. Change calculated as a difference between post-baseline observation and baseline BARS score values.
Time frame: Baseline, Week 2, Week 4, Week 6
Population: ITT; Summarized as Global BARS; individual scores not summarized; (n)=number of subjects with analyzable data at observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in Barnes Akathisia Rating Scale (BARS or BAS) | Week 2 (n=135, 139) | 0.1 scores on scale | Standard Deviation 0.5 |
| Ziprasidone | Change From Baseline in Barnes Akathisia Rating Scale (BARS or BAS) | Week 4 (n=111, 125) | 0.0 scores on scale | Standard Deviation 0.5 |
| Ziprasidone | Change From Baseline in Barnes Akathisia Rating Scale (BARS or BAS) | Week 6 (n=100, 110) | 0.0 scores on scale | Standard Deviation 0.6 |
| Placebo | Change From Baseline in Barnes Akathisia Rating Scale (BARS or BAS) | Week 2 (n=135, 139) | -0.0 scores on scale | Standard Deviation 0.4 |
| Placebo | Change From Baseline in Barnes Akathisia Rating Scale (BARS or BAS) | Week 4 (n=111, 125) | 0.0 scores on scale | Standard Deviation 0.5 |
| Placebo | Change From Baseline in Barnes Akathisia Rating Scale (BARS or BAS) | Week 6 (n=100, 110) | -0.0 scores on scale | Standard Deviation 0.5 |
Comparison: Week 2; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.019395% CI: [0.02, 0.23]ANCOVA
Comparison: Week 4; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.47450.16% CI: [-0.07, 0.16]ANCOVA
Comparison: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.261395% CI: [-0.05, 0.19]ANCOVA
Other Pre-specified
Change From Baseline in Simpson Angus Scale (SAS) Score
SAS is a clinician rated 10-item scale to measure extrapyramidal side effects (Parkinsonism or Parkinsonian side effects induced with antipsychotics); rated on a 5-point scale with range 0 (absence of condition) to 4 (presence of condition in extreme form). Global score is sum of all scores divided by the total number of items. Change calculated as a difference between post-baseline observation and baseline SAS score values.
Time frame: Baseline, Week 2, Week 4, Week 6
Population: ITT; (n)=number of subjects with analyzable data at baseline and post-baseline observation for ziprasidone and placebo, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ziprasidone | Change From Baseline in Simpson Angus Scale (SAS) Score | Week 2 (n=136, 141) | 0.1 scores on scale | Standard Deviation 0.8 |
| Ziprasidone | Change From Baseline in Simpson Angus Scale (SAS) Score | Week 4 (n=111, 126) | 0.0 scores on scale | Standard Deviation 0.8 |
| Ziprasidone | Change From Baseline in Simpson Angus Scale (SAS) Score | Week 6 (n=100, 110) | 0.0 scores on scale | Standard Deviation 0.7 |
| Placebo | Change From Baseline in Simpson Angus Scale (SAS) Score | Week 2 (n=136, 141) | -0.1 scores on scale | Standard Deviation 0.7 |
| Placebo | Change From Baseline in Simpson Angus Scale (SAS) Score | Week 4 (n=111, 126) | 0.0 scores on scale | Standard Deviation 0.6 |
| Placebo | Change From Baseline in Simpson Angus Scale (SAS) Score | Week 6 (n=100, 110) | -0.1 scores on scale | Standard Deviation 0.7 |
Comparison: Week 2; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.009695% CI: [0.04, 0.31]ANCOVA
Comparison: Week 4; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.813495% CI: [-0.13, 0.16]ANCOVA
Comparison: Week 6; Observed cases; Analysis of covariance model with treatment, country, type of mood stabilizer as fixed effects and baseline score as covariate.p-value: 0.022695% CI: [0.02, 0.29]ANCOVA