Schizophrenia
Conditions
Brief summary
Schizophrenia is a brain disease. The condition may be associated with acute psychotic episodes and long-term disability despite remission from the acute symptoms. Current management of schizophrenia focuses on the treatment of acute symptoms as well as long-term treatment aimed at preventing relapse after patients have experienced an improvement in acute symptoms. Patients who discontinue treatment have a high likelihood of experiencing relapse within 1-2 years after an acute episode of schizophrenia. Patients who remain on antipsychotic treatment have lower rates of relapse and have milder courses of exacerbation when relapse occurs.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. Asenapine may help to correct the imbalance in dopamine and serotonin. The purpose of this clinical trial is to evaluate the efficacy of asenapine in preventing relapse/impending relapse (hereafter referred to as 'relapse') in subjects who have been treated with asenapine for symptoms of schizophrenia for 26 weeks. In addition, to determine the safety and tolerability of asenapine for up to 1-year of treatment.
Interventions
DRUGAsenapine - Open Label
Open Label Phase: All subjects received 26 weeks of open label asenapine treatment (cross titration period up to first 4 weeks, with target dose of 10 mg twice daily by week 1).
DRUGPlacebo - Double Blind
Double Blind Phase: Following Open Label Phase, matching placebo sublingual twice daily for 26 weeks.
DRUGAsenapine - Double Blind
Double Blind Phase: Following the Open Label Phase, asenapine 5 or 10 mg sublingual twice daily for 26 weeks.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Have a primary diagnosis of schizophrenia * History of at least 1 prior episode of acute schizophrenia in the 3 years preceding screening * History of schizophrenia requiring continuous antipsychotic treatment for at least 1 years preceding screening * Clinically stable at the time of entry defined by at least a 4 week period of stable symptoms Key
Exclusion criteria
* Have an uncontrolled, unstable clinically significant medical condition * History of suicide attempt or significant violence to others in the past 2 years * A substance-induced psychotic disorder or behavioral disturbance thought to be due to substance abuse * Current substance abuse/dependence * Concurrent psychiatric disorder other than schizophrenia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Relapse or an Impending Relapse | time of first relapse up to Day 182 (double blind phase) | A relapse or impending relapse was declared if a subject meets 1 of 3 symptomatic relapse criteria which were all based on a combination of the Positive and Negative Syndrome Scale (PANSS) total score or PANSS items, and Clinical Global Impression-Severity (CGI-S); or if in the opinion of the investigator, the subject's symptoms of schizophrenia had deteriorated to such an extent or the risk of violence to self or others or risk of suicide had increased so that certain prespecified measures were necessary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Early Discontinuation for Any Reason | time of discontinuation up to Day 182 (double blind phase) | The number of days to early discontinuation is the number of days from randomization to early discontinuation from the study for adverse event, relapse or impending relapse that was not considered an adverse event, withdrawal of informed consent, or lost to follow-up (without evidence of relapse). |
Participant flow
Pre-assignment details
Prior to randomization, there was a 26 week open-label phase where 700 subjects received at least one dose of open-label asenapine (out of 831 initially enrolled). Only subjects who had continued stable presentation of symptoms during this phase were randomized into the double-blind phase.
Participants by arm
| Arm | Count |
|---|---|
| Asenapine Baseline for the double-blind period. Subjects received 26 weeks of open label asenapine treatment (cross titration period up to first 4 weeks, with target dose of 10 mg twice daily by week 1), followed by asenapine 5 or 10 mg sublingual twice daily for 26 weeks in the double blind phase. | 194 |
| Placebo Baseline for the double-blind period. Subjects received 26 weeks of open label asenapine treatment (cross titration period up to first 4 weeks, with target dose of 10 mg twice daily by week 1), followed by matching placebo sublingual twice daily for 26 weeks during the double-blind phase. | 192 |
| Total | 386 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 16 | 53 |
| Overall Study | Lost to Follow-up | 3 | 3 |
| Overall Study | OTHER | 11 | 13 |
| Overall Study | Relapse/Impending relapse, non-AE | 10 | 39 |
| Overall Study | Withdrawal by Subject | 19 | 12 |
Baseline characteristics
| Characteristic | Asenapine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 39.2 years STANDARD_DEVIATION 12.53 | 38.7 years STANDARD_DEVIATION 11.64 | 38.9 years STANDARD_DEVIATION 12.08 |
| Sex: Female, Male Female | 89 Participants | 76 Participants | 165 Participants |
| Sex: Female, Male Male | 105 Participants | 116 Participants | 221 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 | 121 / 194 | 127 / 192 | 170 / 314 |
| serious Total, serious adverse events | 6 / 194 | 22 / 192 | 39 / 314 |
Outcome results
Primary
Time to Relapse or an Impending Relapse
A relapse or impending relapse was declared if a subject meets 1 of 3 symptomatic relapse criteria which were all based on a combination of the Positive and Negative Syndrome Scale (PANSS) total score or PANSS items, and Clinical Global Impression-Severity (CGI-S); or if in the opinion of the investigator, the subject's symptoms of schizophrenia had deteriorated to such an extent or the risk of violence to self or others or risk of suicide had increased so that certain prespecified measures were necessary.
Time frame: time of first relapse up to Day 182 (double blind phase)
Population: ITT population, excluding subjects not treated and w/ past enrollment in an asenapine trial. As trial progressed \& subjects discont'd for various reasons, subjects at risk for relapse decreased from 190 each arm (Day 1) to 70 at risk in placebo arm and 135 subjects in asenapine arm (Day 182). Those relapsing \>3 days after last dose also excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Asenapine | Time to Relapse or an Impending Relapse | Days 99 - 105 (N asenapine = 151; N placebo = 99) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 50 - 56 (N asenapine = 166; N placebo = 127) | 1 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 106 - 112 (N asenapine = 151; N placebo = 96) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 1 - 7 (N asenapine = 190; N placebo = 190) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 113 - 119 (N asenapine = 149; N placebo = 95) | 2 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 57 - 63 (N asenapine = 165; N placebo = 123) | 1 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 120 - 126 (N asenapine = 147; N placebo = 87) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 29 - 35 (N asenapine = 175; N placebo = 149) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 127 - 133 (N asenapine = 147; N placebo = 86) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 64 - 70 (N asenapine = 163; N placebo = 120) | 2 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 134 - 140 (N asenapine = 146; N placebo = 84) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 15 - 21 (N asenapine = 183; N placebo = 170) | 2 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 141 - 147 (N asenapine = 145; N placebo = 83) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 148 - 154 (N asenapine = 142; N placebo = 81) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 71 - 77 (N asenapine = 161; N placebo = 117) | 1 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 155 - 161 (N asenapine = 141; N placebo = 75) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 36 - 42 (N asenapine = 175; N placebo = 140) | 1 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 162 - 168 (N asenapine = 139; N placebo = 74) | 1 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 78 - 84 (N asenapine = 160; N placebo = 113) | 2 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 169 - 175 (N asenapine = 137; N placebo = 72) | 2 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 8 - 14 (N asenapine = 188; N placebo = 186) | 1 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 176 - 182 (N asenapine = 135; N placebo = 70) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 183 - 189 (N asenapine = 75; N placebo = 39) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 85 - 91 (N asenapine = 158; N placebo = 110) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 190 - 196 (N asenapine = 9; N placebo = 9) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 43 - 49 (N asenapine = 173; N placebo = 130) | 5 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 197 - 203 (N asenapine = 2; N placebo = 2) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 92 - 98 (N asenapine = 154; N placebo = 104) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 204 - 210 (N asenapine = 0; N placebo = 1) | 0 relapses |
| Asenapine | Time to Relapse or an Impending Relapse | Days 22 - 28 (N asenapine = 180; N placebo = 160) | 2 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 120 - 126 (N asenapine = 147; N placebo = 87) | 1 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 176 - 182 (N asenapine = 135; N placebo = 70) | 1 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 1 - 7 (N asenapine = 190; N placebo = 190) | 3 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 8 - 14 (N asenapine = 188; N placebo = 186) | 14 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 15 - 21 (N asenapine = 183; N placebo = 170) | 9 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 22 - 28 (N asenapine = 180; N placebo = 160) | 8 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 29 - 35 (N asenapine = 175; N placebo = 149) | 7 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 36 - 42 (N asenapine = 175; N placebo = 140) | 8 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 43 - 49 (N asenapine = 173; N placebo = 130) | 2 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 50 - 56 (N asenapine = 166; N placebo = 127) | 4 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 57 - 63 (N asenapine = 165; N placebo = 123) | 1 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 64 - 70 (N asenapine = 163; N placebo = 120) | 3 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 71 - 77 (N asenapine = 161; N placebo = 117) | 4 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 78 - 84 (N asenapine = 160; N placebo = 113) | 2 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 85 - 91 (N asenapine = 158; N placebo = 110) | 4 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 92 - 98 (N asenapine = 154; N placebo = 104) | 4 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 99 - 105 (N asenapine = 151; N placebo = 99) | 2 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 106 - 112 (N asenapine = 151; N placebo = 96) | 1 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 113 - 119 (N asenapine = 149; N placebo = 95) | 3 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 141 - 147 (N asenapine = 145; N placebo = 83) | 1 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 127 - 133 (N asenapine = 147; N placebo = 86) | 1 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 134 - 140 (N asenapine = 146; N placebo = 84) | 0 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 148 - 154 (N asenapine = 142; N placebo = 81) | 5 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 155 - 161 (N asenapine = 141; N placebo = 75) | 1 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 162 - 168 (N asenapine = 139; N placebo = 74) | 0 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 169 - 175 (N asenapine = 137; N placebo = 72) | 1 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 183 - 189 (N asenapine = 75; N placebo = 39) | 0 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 190 - 196 (N asenapine = 9; N placebo = 9) | 0 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 197 - 203 (N asenapine = 2; N placebo = 2) | 0 relapses |
| Placebo | Time to Relapse or an Impending Relapse | Days 204 - 210 (N asenapine = 0; N placebo = 1) | 0 relapses |
Secondary
Time to Early Discontinuation for Any Reason
The number of days to early discontinuation is the number of days from randomization to early discontinuation from the study for adverse event, relapse or impending relapse that was not considered an adverse event, withdrawal of informed consent, or lost to follow-up (without evidence of relapse).
Time frame: time of discontinuation up to Day 182 (double blind phase)
Population: Intent to treat (ITT) population, additionally excluding subjects not treated and excluding subjects with past enrollment in an asenapine trial.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Asenapine | Time to Early Discontinuation for Any Reason | Days 120 - 126 (N asenapine = 148; N placebo = 88) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 204 - 210 (N asenapine = 0; N placebo = 1) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 1 - 7 (N asenapine = 191; N placebo = 191) | 1 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 8 - 14 (N asenapine = 190; N placebo = 189) | 6 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 15 - 21 (N asenapine = 184; N placebo = 175) | 3 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 22 - 28 (N asenapine = 181; N placebo = 165) | 5 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 29 - 35 (N asenapine = 176; N placebo = 154) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 36 - 42 (N asenapine = 176; N placebo = 143) | 3 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 43 - 49 (N asenapine = 173; N placebo = 136) | 7 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 50 - 56 (N asenapine = 166; N placebo = 129) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 57 - 63 (N asenapine = 166; N placebo = 126) | 3 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 64 - 70 (N asenapine = 163; N placebo = 122) | 1 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 71 - 77 (N asenapine = 162; N placebo = 120) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 78 - 84 (N asenapine = 162; N placebo = 116) | 4 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 85 - 91 (N asenapine = 158; N placebo = 113) | 5 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 92 - 98 (N asenapine = 153; N placebo = 105) | 2 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 99 - 105 (N asenapine = 150; N placebo = 100) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 106 - 112 (N asenapine = 150; N placebo = 98) | 1 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 113 - 119 (N asenapine = 149; N placebo = 97) | 1 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 127 - 133 (N asenapine = 148; N placebo = 87) | 2 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 134 - 140 (N asenapine = 146; N placebo = 86) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 141 - 147 (N asenapine = 145; N placebo = 84) | 3 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 148 - 154 (N asenapine = 142; N placebo = 82) | 1 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 155 - 161 (N asenapine = 141; N placebo = 78) | 1 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 162 - 168 (N asenapine = 139; N placebo = 75) | 2 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 169 - 175 (N asenapine = 137; N placebo = 73) | 2 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 176 - 182 (N asenapine = 135; N placebo = 71) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 183 - 189 (N asenapine = 75; N placebo = 39) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 190 - 196 (N asenapine = 9; N placebo = 9) | 0 participants |
| Asenapine | Time to Early Discontinuation for Any Reason | Days 197 - 203 (N asenapine = 2; N placebo = 2) | 0 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 155 - 161 (N asenapine = 141; N placebo = 78) | 3 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 99 - 105 (N asenapine = 150; N placebo = 100) | 2 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 183 - 189 (N asenapine = 75; N placebo = 39) | 0 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 1 - 7 (N asenapine = 191; N placebo = 191) | 2 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 106 - 112 (N asenapine = 150; N placebo = 98) | 1 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 8 - 14 (N asenapine = 190; N placebo = 189) | 14 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 162 - 168 (N asenapine = 139; N placebo = 75) | 1 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 15 - 21 (N asenapine = 184; N placebo = 175) | 10 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 113 - 119 (N asenapine = 149; N placebo = 97) | 8 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 22 - 28 (N asenapine = 181; N placebo = 165) | 11 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 120 - 126 (N asenapine = 148; N placebo = 88) | 1 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 29 - 35 (N asenapine = 176; N placebo = 154) | 11 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 197 - 203 (N asenapine = 2; N placebo = 2) | 0 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 36 - 42 (N asenapine = 176; N placebo = 143) | 7 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 127 - 133 (N asenapine = 148; N placebo = 87) | 0 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 43 - 49 (N asenapine = 173; N placebo = 136) | 7 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 169 - 175 (N asenapine = 137; N placebo = 73) | 1 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 50 - 56 (N asenapine = 166; N placebo = 129) | 3 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 134 - 140 (N asenapine = 146; N placebo = 86) | 1 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 57 - 63 (N asenapine = 166; N placebo = 126) | 4 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 190 - 196 (N asenapine = 9; N placebo = 9) | 0 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 64 - 70 (N asenapine = 163; N placebo = 122) | 2 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 141 - 147 (N asenapine = 145; N placebo = 84) | 1 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 71 - 77 (N asenapine = 162; N placebo = 120) | 4 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 176 - 182 (N asenapine = 135; N placebo = 71) | 1 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 78 - 84 (N asenapine = 162; N placebo = 116) | 3 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 148 - 154 (N asenapine = 142; N placebo = 82) | 3 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 85 - 91 (N asenapine = 158; N placebo = 113) | 8 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 204 - 210 (N asenapine = 0; N placebo = 1) | 0 participants |
| Placebo | Time to Early Discontinuation for Any Reason | Days 92 - 98 (N asenapine = 153; N placebo = 105) | 4 participants |