Schizophrenia
Conditions
Brief summary
Schizophrenia is a brain disease. The primary features of schizophrenia are characterized by Positive symptoms (symptoms that should not be there, inability to think clearly, to distinguish reality from fantasy i.e., hearing voices) and Negative symptoms (a reduction or absence of normal behaviors or emotions, i.e., unable to manage emotions, make decisions and relate to others). Other symptoms include reduced ability to recall and learn new information, difficulty with problem solving, or maintaining productive employment. The symptoms of schizophrenia may be due to an imbalance in chemicals in the brain, primarily dopamine and serotonin, which enables brain cells to communicate with each other. The clinical development of asenapine, as described in the 2007 IDB appears to have antipsychotic activity with superior symptomatic control compared to placebo and an improved safety profile compared to currently available neuroleptics. Its fast dissolving formulation may further add to treatment compliance. While various titration schedules have been used in previous studies, dose increases at 5 mg BID (twice daily) up to 10 mg BID have been well tolerated. Therefore, further exploration in a larger group of subjects with acute exacerbation of schizophrenia using an asenapine flexible dosing design ( 5 or 10 mg BID) will mimic actual clinical practice in a long-term 52-week extension trial.
Interventions
DRUGHaloperidol
2-8 mg BID
DRUGAsenapine
5 or 10 mg BID
Sponsors
Organon and Co
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
* Completed the short-term 041023 trial (NCT00156104) * Continued to meet all demographic and procedural inclusion criteria of the short-term trial upon entry into this long-term extension trial * Sign a written informed consent for the 041513 trial. * Demonstrated an acceptable degree of compliance with trial medication in the short-term trials in the opinion of the investigator
Exclusion criteria
* CGI-S (Clinical Global Impressions of Severity of Illness) score of greater than or equal to 6 (severely psychotic) * Occurrence(s) of AEs (adverse events) or other clinically significant findings that would prohibit their continuation * Met any of
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Loss of Effect Over Time | Throughout the 52 weeks of the trial. | Loss of effect in subjects who had \>=30% decrease from baseline in Positive and Negative Syndrome Scale (PANSS) score at the end of the original trial (NCT00156104) preceding the long-term extension. PANSS is a 30-item clinician-rated instrument for assessing symptoms of schizophrenia. Scores range from 30-210; higher scores indicate greater severity. Loss of effect = increase in total PANSS \>=30% from start of current study; subjective worsening of schizophrenia/request for dose increase; Clinical Global Impressions of Severity of Illness score \>=6; discontinuation for lack of efficacy. |
| Median Survival Time of Effect | 52 Weeks | Kaplan-Meier estimate of median time to loss of effect in subjects who had \>=30% decrease from baseline in PANSS score at the end of the original trial (NCT00156104) preceding the long-term extension. PANSS is a 30-item clinician-rated instrument for assessing symptoms of schizophrenia. Scores range from 30-210; higher scores indicate greater severity. Loss of effect = increase in total PANSS \>=30% from start of current study; subjective worsening of schizophrenia/request for dose increase; Clinical Global Impressions of Severity of Illness score \>=6; discontinuation for lack of efficacy. |
Participant flow
Pre-assignment details
Note that one participant in each of the Placebo/Asenapine and Asenapine/Asenapine groups was enrolled but did not receive treatment. Thus, the numbers who started the period will be greater than the numbers presented at baseline and for analysis.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Asenapine Placebo in Original Study (NCT00156104) and Asenapine 5 or 10 mg BID (twice daily) in Current Long-Term Extension | 50 |
| Asenapine/Asenapine Asenapine 5 or 10 mg BID in Original Study and in Current Long-Term Extension | 92 |
| Haloperidol/Haloperidol Haloperidol 2-8 mg BID in Original Study and in Current Long-Term Extension | 43 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 11 | 4 |
| Overall Study | Enrolled But Never Received Treatment | 1 | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 9 | 3 |
| Overall Study | Lost to Follow-up | 5 | 7 | 1 |
| Overall Study | Other | 2 | 9 | 3 |
| Overall Study | Withdrawal by Subject | 13 | 26 | 16 |
Baseline characteristics
| Characteristic | Placebo/Asenapine | Asenapine/Asenapine | Haloperidol/Haloperidol | Total |
|---|---|---|---|---|
| Age, Continuous | 41.3 years STANDARD_DEVIATION 12.6 | 35.3 years STANDARD_DEVIATION 10.4 | 39.9 years STANDARD_DEVIATION 11.6 | 38.0 years STANDARD_DEVIATION 11.6 |
| Sex: Female, Male Female | 22 Participants | 37 Participants | 25 Participants | 84 Participants |
| Sex: Female, Male Male | 28 Participants | 55 Participants | 18 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 50 | 54 / 92 | 25 / 43 |
| serious Total, serious adverse events | 12 / 50 | 13 / 92 | 6 / 43 |
Outcome results
Primary
Loss of Effect Over Time
Loss of effect in subjects who had \>=30% decrease from baseline in Positive and Negative Syndrome Scale (PANSS) score at the end of the original trial (NCT00156104) preceding the long-term extension. PANSS is a 30-item clinician-rated instrument for assessing symptoms of schizophrenia. Scores range from 30-210; higher scores indicate greater severity. Loss of effect = increase in total PANSS \>=30% from start of current study; subjective worsening of schizophrenia/request for dose increase; Clinical Global Impressions of Severity of Illness score \>=6; discontinuation for lack of efficacy.
Time frame: Throughout the 52 weeks of the trial.
Population: These are participants who completed the original acute-phase trial (41023) with a decrease from baseline in Positive and Negative Syndrome Scale (PANSS) score \>= 30%, received at least one dose in the current long-term extension, and had at least one post-baseline PANSS assessment during the extension.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo/Asenapine | Loss of Effect Over Time | >Week 32 to Week 36 | 0 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 12 to Week 16 | 3 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 44 to Week 48 | 0 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 28 to Week 32 | 1 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 16 to Week 20 | 0 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 2 to Week 4 | 1 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 24 to Week 28 | 0 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 20 to Week 24 | 0 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 48 to Week 52 | 2 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 40 to Week 44 | 0 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 4 to Week 8 | 3 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 1 to Week 2 | 3 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 36 to Week 40 | 0 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | >Week 8 to Week 12 | 2 Participants |
| Placebo/Asenapine | Loss of Effect Over Time | <=Week 1 | 7 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 36 to Week 40 | 0 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | <=Week 1 | 15 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 1 to Week 2 | 4 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 2 to Week 4 | 14 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 4 to Week 8 | 3 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 8 to Week 12 | 1 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 12 to Week 16 | 1 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 16 to Week 20 | 1 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 20 to Week 24 | 3 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 24 to Week 28 | 1 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 28 to Week 32 | 3 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 32 to Week 36 | 0 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 40 to Week 44 | 0 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 44 to Week 48 | 0 Participants |
| Asenapine/Asenapine | Loss of Effect Over Time | >Week 48 to Week 52 | 5 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 8 to Week 12 | 1 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 44 to Week 48 | 0 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 32 to Week 36 | 0 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 4 to Week 8 | 1 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 28 to Week 32 | 1 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 36 to Week 40 | 1 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 2 to Week 4 | 3 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | <=Week 1 | 6 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 40 to Week 44 | 0 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 20 to Week 24 | 0 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 16 to Week 20 | 1 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 1 to Week 2 | 4 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 24 to Week 28 | 0 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 12 to Week 16 | 4 Participants |
| Haloperidol/Haloperidol | Loss of Effect Over Time | >Week 48 to Week 52 | 2 Participants |
95% CI: [0.6912, 0.9644]
95% CI: [0.7744, 0.955]
95% CI: [0.7631, 0.9952]
Primary
Median Survival Time of Effect
Kaplan-Meier estimate of median time to loss of effect in subjects who had \>=30% decrease from baseline in PANSS score at the end of the original trial (NCT00156104) preceding the long-term extension. PANSS is a 30-item clinician-rated instrument for assessing symptoms of schizophrenia. Scores range from 30-210; higher scores indicate greater severity. Loss of effect = increase in total PANSS \>=30% from start of current study; subjective worsening of schizophrenia/request for dose increase; Clinical Global Impressions of Severity of Illness score \>=6; discontinuation for lack of efficacy.
Time frame: 52 Weeks
Population: These are participants who completed the original acute-phase trial (41023) with a decrease from baseline in Positive and Negative Syndrome Scale (PANSS) score \>= 30%, received at least one dose in the current long-term extension, and had at least one post-baseline PANSS assessment during the extension.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo/Asenapine | Median Survival Time of Effect | 57 Days |
| Asenapine/Asenapine | Median Survival Time of Effect | 31 Days |
| Haloperidol/Haloperidol | Median Survival Time of Effect | 85 Days |