Schizophrenia
Conditions
Keywords
Schizophrenia, Mental Disorders, Antipsychotic Agents, Iloperidone, Relapse Prevention
Brief summary
The purpose of this study is to determine whether Iloperidone is effective in the prevention of relapse in patients with schizophrenia
Interventions
DRUGIloperidone
Over-encapsulated iloperidone tablets were administered orally using a bid schedule; the strengths used include 1, 2, 4, 6, 8, 10, and 12 mg.
DRUGPlacebo
Matching placebo capsules were administered orally using a bid schedule during the double-blind period.
Sponsors
Vanda Pharmaceuticals
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 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients must understand and be capable to communicate adequately with the study coordinator and to participate in cognitive testing. * Patients must agree to cooperate with all tests and examinations required by the protocol, be willing to comply fully with treatment and able to ingest oral medication. * Patients must understand the nature of the study and must sign an informed consent document. * Patients will have a clear diagnosis of schizophrenia according to DSM-IV criteria for at least 1 year. * Patients must need of ongoing psychiatric treatment and must have a documented reason why a change in treatment is needed which might lead to a clinical improvement * At screening patients will have a Positive and Negative Syndrome Scale (PANSS) of no more than 100 and a Clinical Global Impression Scale (CGI) of no more than 5 (i.e. must not be severely ill or worse). * Patients must be outpatients at the time of screening and have not been an inpatient to treat schizophrenia for at least 1 week prior to the screening visit. * Patients must have a history of at least 2 prior episodes of relapse or impending relapse in the 2 years preceding the screening visit.
Exclusion criteria
- * Pregnant or nursing (lactating) women, or women who plan on conceiving during the course of the study. * Patients who meet the DSM-IV criteria for schizophreniform disorder (295.40) and schizoaffective (295.70). * Patients with active symptoms of any other primary psychiatric diagnosis (Axis I) or prominent Axis II disorder which would interfere with compliance to the protocol. * Patients who have a diagnosis or history suggestive of chemical dependence, or drug-induced toxic psychosis in the preceding 6 months; diagnosis or history of abuse (except for nicotine and caffeine) within the past 3 months, or a clinical presentation possibly confounded by the use of recreational drugs or alcohol. * Patients who have a positive urine drug screen (at the screening visit). If opiates are positive at screening and clearly due to the use of pain killing medication, the patient may be re screened after the medication has been discontinued and enrolled in the study if urine drug screen is negative. * Note: Occasional users of recreational drugs other than cocaine, amphetamines, hallucinogens, or parenteral drugs may be recruited. Patients who are dependent on nicotine, caffeine, or theophylline are allowed to enter the study. * Patients who are mentally disabled (moderate to severe). * Patients who have had a history of being in a coma for more than 24 hrs. * Patients who have had thoughts of committing suicide within 6 months prior to screening or at baseline or suicide behaviors within 2 years prior to screening or at baseline. * Patients thought to be of imminent risk of harm to others or in imminent legal difficulty. * Patients under any form of legal compulsion to remain hospitalized or undergo treatment or assessment. * Patients who have any disability that prevent them from completing any of the study requirements. * Patients with a known clinically significant ECG abnormality including PR interval \>240 msec, QRS complex \>110 msec, QTcF \>=450 msec, or congenital long QT syndrome based on central ECG reading results * Treatment naive, first episode patients, * Patients taking iloperidone at the screening visit or with a known hypersensitivity to drugs chemically related to benzioxazoles. * Note: Active medical conditions that are minor or well-controlled are not exclusionary if they do not affect risk to the patient or the study results. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Relapse or Impending Relapse | Up to 26 weeks post-randomization | Relapse or impending relapse was defined as any of the following: hospitalization due to worsening of schizophrenia; increase (worsening) of the PANSS total score of greater than or equal to 30% from randomization, PANSS total score confirmed at a second visit conducted within 1-7 days; clinically significant emergent or worsening suicidal, homicidal, or aggressive behavior; a CGI-Improvement (CGI-I) score of 6 (much worse) or 7 (very much worse) after randomization; a dose increase in study medication or a need for additional open-label antipsychotic treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PANSS Total Score, Change From Baseline to Last Visit | Up to 26 weeks post-randomization | The 30-item Positive and Negative Syndrome Scale (PANSS) was developed to assess the severity of symptoms of schizophrenia. The PANSS items are divided into positive, negative, and general psychopathology factors. All items were rated on a scale of 1 (absent) to 7 (extremely severe). The PANSS total score (or rating) is the sum of all 30 PANSS items taken together (the sum of its 3 subscales), with a maximum score of 210. Change from baseline is calculated as post value minus baseline value. A negative change indicates improvement. |
| CGI-S, Last Visit | Up to 26 weeks post-randomization | The 7-item Clinical Global Impression of Severity (CGI-S) scale was developed to assess the overall, absolute degree of illness at any point in time. A rating of 1 is equivalent to normal, not at all ill, and a rating of 7 is equivalent to among the most extremely ill patients. |
| SDS Total Score, Change From Baseline to Last Visit | Up to 26 weeks post-randomization | The Sheehan Disability Scale (SDS) a self-reported measure that was developed to assess functional impairment in 3 inter-related domains (i.e., work/school, social, and family life). It is a 10-point visual analog scale with 0 being not impaired at all and 10 extremely impaired. Change from baseline is calculated as post value minus baseline value. A negative change indicates improvement. |
Countries
India, Ukraine, United States
Participant flow
Pre-assignment details
A total of 635 patients were enrolled and received iloperidone in the Cross-Titration Phase and entered Stabilization Phase. A total of 303 were randomized and received either iloperidone (n=153) or placebo (n=150) in the Double-Blind Relapse Prevention Phase.
Participants by arm
| Arm | Count |
|---|---|
| Iloperidone oral, open-label titration up to 12 mg for 1-week followed by open-label flexible dosing (8-24 mg/day), followed by double-blind 8-24 mg/day dosing for 26 weeks | 153 |
| Placebo oral, matching placebo administered during double-blind phase for up to 26 weeks | 150 |
| Total | 303 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Cross-Titration and Stabilization Phase | Abnormal Laboratory Value | 25 | 0 |
| Cross-Titration and Stabilization Phase | Abnormal test | 6 | 0 |
| Cross-Titration and Stabilization Phase | Administrative problems | 30 | 0 |
| Cross-Titration and Stabilization Phase | Adverse Event | 92 | 0 |
| Cross-Titration and Stabilization Phase | Death | 1 | 0 |
| Cross-Titration and Stabilization Phase | Lack of Efficacy | 28 | 0 |
| Cross-Titration and Stabilization Phase | Lost to Follow-up | 24 | 0 |
| Cross-Titration and Stabilization Phase | Protocol Violation | 13 | 0 |
| Cross-Titration and Stabilization Phase | Withdrawal by Subject | 107 | 0 |
| Double-blind Relapse Prevention Phase | Abnormal Laboratory Value | 4 | 2 |
| Double-blind Relapse Prevention Phase | Abnormal test | 1 | 0 |
| Double-blind Relapse Prevention Phase | Administrative problems | 45 | 29 |
| Double-blind Relapse Prevention Phase | Adverse Event | 5 | 0 |
| Double-blind Relapse Prevention Phase | Death | 1 | 0 |
| Double-blind Relapse Prevention Phase | Lack of Efficacy | 0 | 2 |
| Double-blind Relapse Prevention Phase | Lost to Follow-up | 6 | 4 |
| Double-blind Relapse Prevention Phase | Protocol Violation | 1 | 1 |
| Double-blind Relapse Prevention Phase | Withdrawal by Subject | 14 | 10 |
Baseline characteristics
| Characteristic | Iloperidone | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 38.4 years STANDARD_DEVIATION 11.3 | 38.2 years STANDARD_DEVIATION 11.1 | 38.3 years STANDARD_DEVIATION 11.2 |
| Race/Ethnicity, Customized Asian | 38 Participants | 40 Participants | 78 Participants |
| Race/Ethnicity, Customized Black | 31 Participants | 28 Participants | 59 Participants |
| Race/Ethnicity, Customized Caucasian | 74 Participants | 77 Participants | 151 Participants |
| Race/Ethnicity, Customized Other | 9 Participants | 5 Participants | 14 Participants |
| Race/Ethnicity, Customized Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 57 Participants | 68 Participants | 125 Participants |
| Sex: Female, Male Male | 96 Participants | 82 Participants | 178 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 629 | 1 / 151 | 0 / 150 |
| other Total, other adverse events | 244 / 629 | 16 / 151 | 30 / 150 |
| serious Total, serious adverse events | 21 / 629 | 6 / 151 | 4 / 150 |
Outcome results
Primary
Time to Relapse or Impending Relapse
Relapse or impending relapse was defined as any of the following: hospitalization due to worsening of schizophrenia; increase (worsening) of the PANSS total score of greater than or equal to 30% from randomization, PANSS total score confirmed at a second visit conducted within 1-7 days; clinically significant emergent or worsening suicidal, homicidal, or aggressive behavior; a CGI-Improvement (CGI-I) score of 6 (much worse) or 7 (very much worse) after randomization; a dose increase in study medication or a need for additional open-label antipsychotic treatment.
Time frame: Up to 26 weeks post-randomization
Population: Two subjects lost to follow-up after randomization were excluded from the analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Iloperidone | Time to Relapse or Impending Relapse | NA Days |
| Placebo | Time to Relapse or Impending Relapse | 99 Days |
p-value: <0.000195% CI: [3.2, 8.4]Log Rank
Secondary
CGI-S, Last Visit
The 7-item Clinical Global Impression of Severity (CGI-S) scale was developed to assess the overall, absolute degree of illness at any point in time. A rating of 1 is equivalent to normal, not at all ill, and a rating of 7 is equivalent to among the most extremely ill patients.
Time frame: Up to 26 weeks post-randomization
Population: Data presented are FAS (Full Analysis set) OC (observed cases), as this measure does not include a baseline assessment; RP Completion visit includes observations from last visit during DBRP period for patients who completed the study and RP Completion visit that could not be remapped to a previous scheduled visit for patients who discontinued the DBRP phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iloperidone | CGI-S, Last Visit | 3.0 units on a scale | Standard Deviation 0.89 |
| Placebo | CGI-S, Last Visit | 3.6 units on a scale | Standard Deviation 1.11 |
Secondary
PANSS Total Score, Change From Baseline to Last Visit
The 30-item Positive and Negative Syndrome Scale (PANSS) was developed to assess the severity of symptoms of schizophrenia. The PANSS items are divided into positive, negative, and general psychopathology factors. All items were rated on a scale of 1 (absent) to 7 (extremely severe). The PANSS total score (or rating) is the sum of all 30 PANSS items taken together (the sum of its 3 subscales), with a maximum score of 210. Change from baseline is calculated as post value minus baseline value. A negative change indicates improvement.
Time frame: Up to 26 weeks post-randomization
Population: Data presented are FAS (Full Analysis set) LOCF (last observation carried forward) Change From DBRP (Double-Blind Relapse Prevention) Baseline to RP Completion. RP Completion visit includes observations from last visit during DBRP period for patients who completed the study or RP Completion visit for patients who discontinued the DBRP phase and not included in previous scheduled visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iloperidone | PANSS Total Score, Change From Baseline to Last Visit | 1.1 units on a scale | Standard Error 1.12 |
| Placebo | PANSS Total Score, Change From Baseline to Last Visit | 12.4 units on a scale | Standard Error 1.15 |
p-value: <0.0001ANCOVA
Secondary
SDS Total Score, Change From Baseline to Last Visit
The Sheehan Disability Scale (SDS) a self-reported measure that was developed to assess functional impairment in 3 inter-related domains (i.e., work/school, social, and family life). It is a 10-point visual analog scale with 0 being not impaired at all and 10 extremely impaired. Change from baseline is calculated as post value minus baseline value. A negative change indicates improvement.
Time frame: Up to 26 weeks post-randomization
Population: Data presented are FAS (Full Analysis set) LOCF (last observation carried forward) Change From DBRP (Double-Blind Relapse Prevention) Baseline to RP Completion. RP Completion visit includes observations from last visit during DBRP period for patients who completed the study or RP Completion visit for patients who discontinued the DBRP phase and not included in previous scheduled visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iloperidone | SDS Total Score, Change From Baseline to Last Visit | -0.2 units on a scale | Standard Error 0.54 |
| Placebo | SDS Total Score, Change From Baseline to Last Visit | 1.8 units on a scale | Standard Error 0.61 |
p-value: 0.0062ANCOVA