Schizophrenia
Conditions
Keywords
Schizophrenia, iloperidone, switch, gradual switch, immediate switch
Brief summary
Evaluate the clinical outcome of two switching strategies to iloperidone treatment in adult subjects with schizophrenia who require a change in their current antipsychotic treatment of risperidone, olanzapine, or aripiprazole due to suboptimal efficacy and/or safety/tolerability reasons.
Interventions
DRUGiloperidone
Iloperidone tablets supplied at doses of 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg to achieve a target dose of 12-24 mg/day for 12 weeks.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Males or females, 18 to 64 years of age, inclusive * DSM-IV diagnosis of schizophrenia * Patients currently on an optimal in-label dose of one of the following permitted antipsychotic treatments for at least 30 days: risperidone, olanzapine, or aripiprazole * Efficacy Clinical Global Impression of Severity (E-CGI-S) of 4 or 5 or * Not tolerating one of the permitted treatments and exhibits one of the allowable side-effects
Exclusion criteria
* Any other current Axis I disorder other than schizophrenia which is the focus of treatment; * Acutely psychotic or patient's symptom severity requires hospitalization * Patient with significant cardiovascular illness (myocardial infarction, cardiac arrhythmia) Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Integrated Clinical Global Impression of Change (I-CGI-C) at Week 12 | Week 12 | The I-CGI-C at Week 12 was the overall impression of medically qualified raters using three separate Clinical Global Impression of Change scales: efficacy (E-CGI-C); safety and tolerability (ST-CGI-S); and overall severity (I-CGI-S) combined for a total score. The I-CGI-C scale ranged from 1 to 7 with lower scores indicating improvement (1=very much improved, 2=much improved, 3=minimally improved), higher scores indicating worsening (5=minimally worse, 6= much worse, 7=very much worse), and a score of 4 indicating no change. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12 | Baseline, Week 12 | The TSQM consisted of 14 questions about the patient's satisfaction with the drug in 4 domains: Effectiveness \[3 questions scored as 1(extremely dissatisfied) to 7(extremely satisfied)\], Side Effects \[question 4 scored as 0(no) or 1(yes);question 5 scored as 1(extremely bothersome) to 5(not at all bothersome);questions 6 - 8 scored as 1(a great deal) to 5(not at all)\], Convenience \[questions 9 and 10 scored as 1(extremely difficult) to 7 (extremely easy);question 11 scored as 1(extremely inconvenient) to 5 (extremely convenient)\] and Global Satisfaction \[question 12 scored as 1(not at all confident) to 7(extremely confident);question 13 scored as 1(not at all certain) to 5(extremely certain);question 14 scored as 1(extremely dissatisfied) to 5(extremely satisfied)\]. The scores of each of the domains were added together and an algorithm used to create a score of 0 to 100. Higher scores for each domain indicate a better outcome. A positive change from baseline indicates improvement. |
| Number of Participants With Adverse Events, Serious Adverse Events or Death | 12 Weeks | Adverse event are defined as any unfavorable and unintended diagnosis, symptoms, sign (including an abnormal lab finding), syndrome or disease which either occurs during the study, having been absent at baseline, or if present at baseline appear to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization , cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgments of the investigators represent significant hazards. Additional information about adverse events can be found in the Adverse Event section. |
| Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12 | Baseline, Week 12 | Medically qualified raters use the E-CGI-S scale at Baseline and Week 12 to assess the effectiveness of treatment by examining changes in positive symptoms \[hallucinations (false perceptions), delusions (false beliefs), paranoia (unfounded distrust), conceptual disorganization (loosening of associations), or hostility\], negative symptoms \[apathy (lack of interest), avolition (lack of motivation), alogia (poverty of speech), and anhedonia (absence of pleasure)\] and cognitive symptoms \[concentration difficulties, difficulties with executive function (integrative reasoning), and illogical thinking\] in the previous 7 days on a scale of 1 to 7 (1=normal, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill or 7=among the most extremely ill). A negative change from baseline indicates improvement. |
| Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12 | Baseline, Week 12 | Medically qualified raters used the ST-CGI-S at Baseline and Week 12 to evaluate safety and tolerability in the previous 7 days on a scale of 1 to 7 (1=Normal-no symptoms, 2=borderline severity, 3=mild impairment, 4=moderate, 5=marked, 6=severe, 7=among the most severe.) A negative change from baseline indicates improvement. |
| Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12 | Baseline, Week 12 | I-CGI-S incorporated the overall, combined impression of illness severity based upon the E-CGI-S and ST-CGI-S. Medically qualified raters evaluated the patient's illness in the previous 7 days at Baseline and Week 12 on a scale of 1 to 7 (1=normal not at all ill, 2=borderline mental illness or impairment, 3=mildly ill or impaired, 4=moderately ill or impaired, 5=marked ill or impaired, 6= severely ill or impaired or 7=among the most extremely ill patients. A negative change from baseline indicates improvement. |
Countries
United States
Participant flow
Pre-assignment details
500 participants taking antipsychotic drugs: 175 participants in the risperidone cohort, 155 participants in the olanzapine cohort and 170 participants in the aripiprazole cohort were randomized and received study drug in one of two iloperidone treatment arms: gradual switch or immediate switch. 1 randomized participant did not receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| Iloperidone Gradual Switch Participants taking risperidone, olanzapine or aripiprazole gradually decreased the dose they were taking: 50% of original dose on Day 1, 25% of original dose after the first week and the total discontinuation of the drug after the second week.
On Day 1 participants began taking iloperidone orally twice a day (bid) in the morning and in the evening beginning at a dose of 1 mg and increasing to 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg bid on consecutive days over a 7-day period to achieve a total dose of 12-24 mg/day for 12 weeks. | 240 |
| Iloperidone Immediate Switch Participants taking risperidone, olanzapine or aripiprazole discontinued the drug immediately.
On Day 1 participants began taking iloperidone orally twice a day (bid) in the morning and in the evening beginning at a dose of 1 mg and increasing to 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg bid on consecutive days over a 7-day period to achieve a total dose of 12-24 mg/day for 12 weeks. | 260 |
| Total | 500 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal test procedure results | 0 | 1 |
| Overall Study | Administrative problems | 1 | 1 |
| Overall Study | Adverse Event | 25 | 39 |
| Overall Study | Lost to Follow-up | 15 | 17 |
| Overall Study | Patient withdrew consent | 14 | 11 |
| Overall Study | Protocol deviation | 12 | 9 |
| Overall Study | Randomized in error | 1 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 5 | 4 |
Baseline characteristics
| Characteristic | Iloperidone Gradual Switch | Iloperidone Immediate Switch | Total |
|---|---|---|---|
| Age Continuous | 42.3 years STANDARD_DEVIATION 10.98 | 44.2 years STANDARD_DEVIATION 10.92 | 43.3 years STANDARD_DEVIATION 10.98 |
| Sex: Female, Male Female | 70 Participants | 95 Participants | 165 Participants |
| Sex: Female, Male Male | 170 Participants | 165 Participants | 335 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 148 / 240 | 155 / 260 |
| serious Total, serious adverse events | 8 / 240 | 7 / 260 |
Outcome results
Primary
Integrated Clinical Global Impression of Change (I-CGI-C) at Week 12
The I-CGI-C at Week 12 was the overall impression of medically qualified raters using three separate Clinical Global Impression of Change scales: efficacy (E-CGI-C); safety and tolerability (ST-CGI-S); and overall severity (I-CGI-S) combined for a total score. The I-CGI-C scale ranged from 1 to 7 with lower scores indicating improvement (1=very much improved, 2=much improved, 3=minimally improved), higher scores indicating worsening (5=minimally worse, 6= much worse, 7=very much worse), and a score of 4 indicating no change.
Time frame: Week 12
Population: Participants from the Full Analysis Set (three cohorts combined: risperidone, olanzapine or aripiprazole) with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iloperidone Gradual Switch | Integrated Clinical Global Impression of Change (I-CGI-C) at Week 12 | 2.826 Score on a scale | Standard Deviation 1.1244 |
| Iloperidone Immediate Switch | Integrated Clinical Global Impression of Change (I-CGI-C) at Week 12 | 2.824 Score on a scale | Standard Deviation 1.33 |
Secondary
Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12
I-CGI-S incorporated the overall, combined impression of illness severity based upon the E-CGI-S and ST-CGI-S. Medically qualified raters evaluated the patient's illness in the previous 7 days at Baseline and Week 12 on a scale of 1 to 7 (1=normal not at all ill, 2=borderline mental illness or impairment, 3=mildly ill or impaired, 4=moderately ill or impaired, 5=marked ill or impaired, 6= severely ill or impaired or 7=among the most extremely ill patients. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Iloperidone Gradual Switch | Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12 | Change from baseline 3 cohorts combined | -0.9 Score on a scale | Standard Deviation 0.95 |
| Iloperidone Gradual Switch | Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12 | Change from baseline risperidone cohort (n=81,92) | -0.9 Score on a scale | Standard Deviation 0.85 |
| Iloperidone Gradual Switch | Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12 | Change from baseline olanzapine cohort (n=77,74) | -0.8 Score on a scale | Standard Deviation 0.96 |
| Iloperidone Gradual Switch | Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12 | Change from baseline aripiprazole cohort (n=77,80) | -1.0 Score on a scale | Standard Deviation 1.04 |
| Iloperidone Immediate Switch | Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12 | Change from baseline aripiprazole cohort (n=77,80) | -0.9 Score on a scale | Standard Deviation 1.04 |
| Iloperidone Immediate Switch | Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12 | Change from baseline 3 cohorts combined | -0.9 Score on a scale | Standard Deviation 0.97 |
| Iloperidone Immediate Switch | Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12 | Change from baseline olanzapine cohort (n=77,74) | -0.7 Score on a scale | Standard Deviation 0.98 |
| Iloperidone Immediate Switch | Change From Baseline in Integrated Clinical Global Impression of Severity (I-CGI-S) at Week 12 | Change from baseline risperidone cohort (n=81,92) | -1.0 Score on a scale | Standard Deviation 0.89 |
Secondary
Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12
Medically qualified raters use the E-CGI-S scale at Baseline and Week 12 to assess the effectiveness of treatment by examining changes in positive symptoms \[hallucinations (false perceptions), delusions (false beliefs), paranoia (unfounded distrust), conceptual disorganization (loosening of associations), or hostility\], negative symptoms \[apathy (lack of interest), avolition (lack of motivation), alogia (poverty of speech), and anhedonia (absence of pleasure)\] and cognitive symptoms \[concentration difficulties, difficulties with executive function (integrative reasoning), and illogical thinking\] in the previous 7 days on a scale of 1 to 7 (1=normal, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill or 7=among the most extremely ill). A negative change from baseline indicates improvement.
Time frame: Baseline, Week 12
Population: Participants from the Full Analysis Set with data available for analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Iloperidone Gradual Switch | Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12 | Change from baseline 3 cohorts combined | -0.8 Score on a scale | Standard Deviation 0.89 |
| Iloperidone Gradual Switch | Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12 | Change from baseline olanzapine cohort (n=77,74) | -0.8 Score on a scale | Standard Deviation 0.96 |
| Iloperidone Gradual Switch | Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12 | Change from baseline risperidone cohort (n=81,92) | -0.9 Score on a scale | Standard Deviation 0.82 |
| Iloperidone Gradual Switch | Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12 | Change from baseline aripiprazole cohort (n=77,90) | -0.8 Score on a scale | Standard Deviation 0.89 |
| Iloperidone Immediate Switch | Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12 | Change from baseline risperidone cohort (n=81,92) | -0.9 Score on a scale | Standard Deviation 0.85 |
| Iloperidone Immediate Switch | Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12 | Change from baseline 3 cohorts combined | -0.8 Score on a scale | Standard Deviation 0.89 |
| Iloperidone Immediate Switch | Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12 | Change from baseline aripiprazole cohort (n=77,90) | -0.9 Score on a scale | Standard Deviation 0.92 |
| Iloperidone Immediate Switch | Change From Baseline in the Efficacy Clinical Global Impression of Severity (E-CGI-S) at Week 12 | Change from baseline olanzapine cohort (n=77,74) | -0.6 Score on a scale | Standard Deviation 0.88 |
Secondary
Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12
Medically qualified raters used the ST-CGI-S at Baseline and Week 12 to evaluate safety and tolerability in the previous 7 days on a scale of 1 to 7 (1=Normal-no symptoms, 2=borderline severity, 3=mild impairment, 4=moderate, 5=marked, 6=severe, 7=among the most severe.) A negative change from baseline indicates improvement.
Time frame: Baseline, Week 12
Population: Participants from the Full Analysis Set with data available for analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Iloperidone Gradual Switch | Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12 | Change from baseline 3 cohorts combined | -0.9 Score on a scale | Standard Deviation 1.29 |
| Iloperidone Gradual Switch | Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12 | Change from baseline risperidone cohort (n=81,92) | -1.1 Score on a scale | Standard Deviation 1.27 |
| Iloperidone Gradual Switch | Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12 | Change from baseline olanzapine cohort (n=77,74) | -0.9 Score on a scale | Standard Deviation 1.2 |
| Iloperidone Gradual Switch | Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12 | Change from baseline aripiprazole cohort (n=77,90) | -0.8 Score on a scale | Standard Deviation 1.39 |
| Iloperidone Immediate Switch | Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12 | Change from baseline aripiprazole cohort (n=77,90) | -0.4 Score on a scale | Standard Deviation 1.45 |
| Iloperidone Immediate Switch | Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12 | Change from baseline 3 cohorts combined | -0.8 Score on a scale | Standard Deviation 1.45 |
| Iloperidone Immediate Switch | Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12 | Change from baseline olanzapine cohort (n=77,74) | -0.9 Score on a scale | Standard Deviation 1.36 |
| Iloperidone Immediate Switch | Change From Baseline in the Safety and Tolerability Clinical Global Impression of Severity (ST-CGI-S) at Week 12 | Change from baseline risperidone cohort (n=81,92) | -0.9 Score on a scale | Standard Deviation 1.49 |
Secondary
Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12
The TSQM consisted of 14 questions about the patient's satisfaction with the drug in 4 domains: Effectiveness \[3 questions scored as 1(extremely dissatisfied) to 7(extremely satisfied)\], Side Effects \[question 4 scored as 0(no) or 1(yes);question 5 scored as 1(extremely bothersome) to 5(not at all bothersome);questions 6 - 8 scored as 1(a great deal) to 5(not at all)\], Convenience \[questions 9 and 10 scored as 1(extremely difficult) to 7 (extremely easy);question 11 scored as 1(extremely inconvenient) to 5 (extremely convenient)\] and Global Satisfaction \[question 12 scored as 1(not at all confident) to 7(extremely confident);question 13 scored as 1(not at all certain) to 5(extremely certain);question 14 scored as 1(extremely dissatisfied) to 5(extremely satisfied)\]. The scores of each of the domains were added together and an algorithm used to create a score of 0 to 100. Higher scores for each domain indicate a better outcome. A positive change from baseline indicates improvement.
Time frame: Baseline, Week 12
Population: Participants from the Full Analysis Set with data available for analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Iloperidone Gradual Switch | Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12 | Change from baseline 3 cohorts combined | 14.1 Score on a scale | Standard Deviation 29.56 |
| Iloperidone Gradual Switch | Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12 | Change from baseline risperidone cohort (n=75,85) | 14.4 Score on a scale | Standard Deviation 27 |
| Iloperidone Gradual Switch | Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12 | Change from baseline olanzapine cohort (n=70,67) | 13.3 Score on a scale | Standard Deviation 28.17 |
| Iloperidone Gradual Switch | Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12 | Change from baseline aripiprazole cohort (n=69,81) | 14.8 Score on a scale | Standard Deviation 33.72 |
| Iloperidone Immediate Switch | Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12 | Change from baseline aripiprazole cohort (n=69,81) | 11.0 Score on a scale | Standard Deviation 25.12 |
| Iloperidone Immediate Switch | Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12 | Change from baseline 3 cohorts combined | 12.7 Score on a scale | Standard Deviation 27.89 |
| Iloperidone Immediate Switch | Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12 | Change from baseline olanzapine cohort (n=70,67) | 9.9 Score on a scale | Standard Deviation 28.6 |
| Iloperidone Immediate Switch | Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) at Week 12 | Change from baseline risperidone cohort (n=75,85) | 16.6 Score on a scale | Standard Deviation 29.65 |
Secondary
Number of Participants With Adverse Events, Serious Adverse Events or Death
Adverse event are defined as any unfavorable and unintended diagnosis, symptoms, sign (including an abnormal lab finding), syndrome or disease which either occurs during the study, having been absent at baseline, or if present at baseline appear to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization , cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgments of the investigators represent significant hazards. Additional information about adverse events can be found in the Adverse Event section.
Time frame: 12 Weeks
Population: Participants from the Safety Analysis Set- all randomized participants who received study drug (three cohorts combined: risperidone, olanzapine or aripiprazole) with data available for analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Iloperidone Gradual Switch | Number of Participants With Adverse Events, Serious Adverse Events or Death | Serious Adverse Events | 8 Participants |
| Iloperidone Gradual Switch | Number of Participants With Adverse Events, Serious Adverse Events or Death | Adverse Events | 196 Participants |
| Iloperidone Gradual Switch | Number of Participants With Adverse Events, Serious Adverse Events or Death | Death | 0 Participants |
| Iloperidone Immediate Switch | Number of Participants With Adverse Events, Serious Adverse Events or Death | Serious Adverse Events | 7 Participants |
| Iloperidone Immediate Switch | Number of Participants With Adverse Events, Serious Adverse Events or Death | Adverse Events | 207 Participants |
| Iloperidone Immediate Switch | Number of Participants With Adverse Events, Serious Adverse Events or Death | Death | 0 Participants |