Long-Term Efficacy and Safety of Asenapine Using Haloperidol as a Positive Control (41513)(COMPLETED)(P05785)
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 3 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Active Comparator: Haloperidol/Haloperidol Haloperidol in original study (NCT00156104) and in current long-term extension. |
Drug: Haloperidol
2-8 mg BID
|
Experimental: Asenapine/Asenapine Asenapine in original study and asenapine in current long-term extension. |
Drug: Asenapine
5 or 10 mg BID
|
Experimental: Placebo/Asenapine Double-Blind subjects randomized to only placebo medication for 6 weeks in the short-term 041023 asenapine trial, were randomized (double-blind) into the long-term 041513 asenapine extension trial and received asenapine 5 mg BID for Week 1. After Week 1, subjects received asenapine (either 5 mg BID or 10 mg BID) for the remainder of the 52-week trial. |
Drug: Asenapine
5 or 10 mg BID
|
Outcome Measures
Primary Outcome Measures
- 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.
Eligibility Criteria
Criteria
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 exclusion criteria regarding medical/psychiatric status listed in the 041023 short-term trial
-
Met exclusion criteria for medication status in short-term trials except for antidepressants and mood stabilizers.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Organon and Co
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- P05785
- Hera;
- 41513
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail | 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. |
Arm/Group Title | Placebo/Asenapine | Asenapine/Asenapine | Haloperidol/Haloperidol |
---|---|---|---|
Arm/Group Description | Placebo in Original Study (NCT00156104) and Asenapine 5 or 10 mg BID (twice daily) in Current Long-Term Extension | Asenapine 5 or 10 mg BID in Original Study and in Current Long-Term Extension | Haloperidol 2-8 mg BID in Original Study and in Current Long-Term Extension |
Period Title: Overall Study | |||
STARTED | 51 | 93 | 43 |
COMPLETED | 20 | 30 | 16 |
NOT COMPLETED | 31 | 63 | 27 |
Baseline Characteristics
Arm/Group Title | Placebo/Asenapine | Asenapine/Asenapine | Haloperidol/Haloperidol | Total |
---|---|---|---|---|
Arm/Group Description | Placebo in Original Study (NCT00156104) and Asenapine 5 or 10 mg BID (twice daily) in Current Long-Term Extension | Asenapine 5 or 10 mg BID in Original Study and in Current Long-Term Extension | Haloperidol 2-8 mg BID in Original Study and in Current Long-Term Extension | Total of all reporting groups |
Overall Participants | 50 | 92 | 43 | 185 |
Age (years) [Mean (Standard Deviation) ] | ||||
Mean (Standard Deviation) [years] |
41.3
(12.6)
|
35.3
(10.4)
|
39.9
(11.6)
|
38.0
(11.6)
|
Sex: Female, Male (Count of Participants) | ||||
Female |
22
44%
|
37
40.2%
|
25
58.1%
|
84
45.4%
|
Male |
28
56%
|
55
59.8%
|
18
41.9%
|
101
54.6%
|
Outcome Measures
Title | Loss of Effect Over Time |
---|---|
Description | 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. |
Outcome Measure Data
Analysis Population Description |
---|
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/Group Title | Placebo/Asenapine | Asenapine/Asenapine | Haloperidol/Haloperidol |
---|---|---|---|
Arm/Group Description | Placebo in Original Study (NCT00156104) and Asenapine 5 or 10 mg BID (twice daily) in Current Long-Term Extension | Asenapine 5 or 10 mg BID in Original Study and in Current Long-Term Extension | Haloperidol 2-8 mg BID in Original Study and in Current Long-Term Extension |
Measure Participants | 30 | 65 | 29 |
<=Week 1 |
7
14%
|
15
16.3%
|
6
14%
|
>Week 1 to Week 2 |
3
6%
|
4
4.3%
|
4
9.3%
|
>Week 2 to Week 4 |
1
2%
|
14
15.2%
|
3
7%
|
>Week 4 to Week 8 |
3
6%
|
3
3.3%
|
1
2.3%
|
>Week 8 to Week 12 |
2
4%
|
1
1.1%
|
1
2.3%
|
>Week 12 to Week 16 |
3
6%
|
1
1.1%
|
4
9.3%
|
>Week 16 to Week 20 |
0
0%
|
1
1.1%
|
1
2.3%
|
>Week 20 to Week 24 |
0
0%
|
3
3.3%
|
0
0%
|
>Week 24 to Week 28 |
0
0%
|
1
1.1%
|
0
0%
|
>Week 28 to Week 32 |
1
2%
|
3
3.3%
|
1
2.3%
|
>Week 32 to Week 36 |
0
0%
|
0
0%
|
0
0%
|
>Week 36 to Week 40 |
0
0%
|
0
0%
|
1
2.3%
|
>Week 40 to Week 44 |
0
0%
|
0
0%
|
0
0%
|
>Week 44 to Week 48 |
0
0%
|
0
0%
|
0
0%
|
>Week 48 to Week 52 |
2
4%
|
5
5.4%
|
2
4.7%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Placebo/Asenapine |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Kaplan-Meier Estimate of Loss of Effect |
Estimated Value | 0.8619 | |
Confidence Interval |
() 95% 0.6912 to 0.9644 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | 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. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Asenapine/Asenapine |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Kaplan-Meier Estimate of Loss of Effect |
Estimated Value | 0.8834 | |
Confidence Interval |
() 95% 0.7744 to 0.9550 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | 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. |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Haloperidol/Haloperidol |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Kaplan-Meier Estimate of Loss of Effect |
Estimated Value | 0.9376 | |
Confidence Interval |
() 95% 0.7631 to 0.9952 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments | 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. |
Title | Median Survival Time of Effect |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
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/Group Title | Placebo/Asenapine | Asenapine/Asenapine | Haloperidol/Haloperidol |
---|---|---|---|
Arm/Group Description | Placebo in Original Study (NCT00156104) and Asenapine 5 or 10 mg BID (twice daily) in Current Long-Term Extension | Asenapine 5 or 10 mg BID in Original Study and in Current Long-Term Extension | Haloperidol 2-8 mg BID in Original Study and in Current Long-Term Extension |
Measure Participants | 30 | 65 | 29 |
Median (95% Confidence Interval) [Days] |
57
|
31
|
85
|
Adverse Events
Time Frame | Adverse events (AEs) were monitored continually through 52 weeks of treatment and 1 month of posttreatment follow-up. | |||||
---|---|---|---|---|---|---|
Adverse Event Reporting Description | Information regarding AEs was obtained by questioning or examining the subject at each visit, and recording complaints and symptoms. Reports are for all serious AEs and treatment-emergent nonserious AEs. | |||||
Arm/Group Title | Placebo/Asenapine | Asenapine/Asenapine | Haloperidol/Haloperidol | |||
Arm/Group Description | Placebo in Original Study (NCT00156104) and Asenapine 5 or 10 mg BID (twice daily) in Current Long-Term Extension | Asenapine 5 or 10 mg BID in Original Study and in Current Long-Term Extension | Haloperidol 2-8 mg BID in Original Study and in Current Long-Term Extension | |||
All Cause Mortality |
||||||
Placebo/Asenapine | Asenapine/Asenapine | Haloperidol/Haloperidol | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
Placebo/Asenapine | Asenapine/Asenapine | Haloperidol/Haloperidol | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 12/50 (24%) | 13/92 (14.1%) | 6/43 (14%) | |||
Injury, poisoning and procedural complications | ||||||
DRUG EXPOSURE DURING PREGNANCY | 1/50 (2%) | 1 | 1/92 (1.1%) | 1 | 0/43 (0%) | 0 |
MULTIPLE FRACTURES | 0/50 (0%) | 0 | 1/92 (1.1%) | 1 | 0/43 (0%) | 0 |
ROAD TRAFFIC ACCIDENT | 0/50 (0%) | 0 | 1/92 (1.1%) | 1 | 0/43 (0%) | 0 |
Metabolism and nutrition disorders | ||||||
HYPONATREMIA | 0/50 (0%) | 0 | 0/92 (0%) | 0 | 1/43 (2.3%) | 1 |
Nervous system disorders | ||||||
CONVULSION | 0/50 (0%) | 0 | 0/92 (0%) | 0 | 1/43 (2.3%) | 2 |
SYNCOPE | 1/50 (2%) | 1 | 0/92 (0%) | 0 | 0/43 (0%) | 0 |
Psychiatric disorders | ||||||
AGITATION | 0/50 (0%) | 0 | 1/92 (1.1%) | 1 | 0/43 (0%) | 0 |
COMPLETED SUICIDE | 0/50 (0%) | 0 | 1/92 (1.1%) | 1 | 0/43 (0%) | 0 |
SCHIZOPHRENIA | 7/50 (14%) | 8 | 8/92 (8.7%) | 14 | 5/43 (11.6%) | 6 |
SCHIZOPHRENIA, PARANOID TYPE | 3/50 (6%) | 3 | 1/92 (1.1%) | 1 | 0/43 (0%) | 0 |
SUICIDAL IDEATION | 0/50 (0%) | 0 | 1/92 (1.1%) | 1 | 0/43 (0%) | 0 |
SUICIDE ATTEMPT | 0/50 (0%) | 0 | 0/92 (0%) | 0 | 1/43 (2.3%) | 1 |
Respiratory, thoracic and mediastinal disorders | ||||||
RESPIRATORY FAILURE | 0/50 (0%) | 0 | 0/92 (0%) | 0 | 1/43 (2.3%) | 1 |
Surgical and medical procedures | ||||||
ABORTION INDUCED | 1/50 (2%) | 1 | 1/92 (1.1%) | 1 | 0/43 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
Placebo/Asenapine | Asenapine/Asenapine | Haloperidol/Haloperidol | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 28/50 (56%) | 54/92 (58.7%) | 25/43 (58.1%) | |||
Gastrointestinal disorders | ||||||
CONSTIPATION | 4/50 (8%) | 5 | 4/92 (4.3%) | 4 | 3/43 (7%) | 3 |
HYPOAESTHESIA ORAL | 3/50 (6%) | 3 | 0/92 (0%) | 0 | 0/43 (0%) | 0 |
NAUSEA | 3/50 (6%) | 3 | 2/92 (2.2%) | 2 | 6/43 (14%) | 6 |
VOMITING | 2/50 (4%) | 2 | 3/92 (3.3%) | 3 | 3/43 (7%) | 4 |
General disorders | ||||||
ASTHENIA | 5/50 (10%) | 10 | 7/92 (7.6%) | 8 | 6/43 (14%) | 6 |
Infections and infestations | ||||||
INFLUENZA | 3/50 (6%) | 3 | 4/92 (4.3%) | 4 | 3/43 (7%) | 4 |
Investigations | ||||||
ALANINE AMINOTRANSFERASE INCREASED | 0/50 (0%) | 0 | 6/92 (6.5%) | 6 | 1/43 (2.3%) | 1 |
WEIGHT DECREASED | 2/50 (4%) | 2 | 5/92 (5.4%) | 6 | 0/43 (0%) | 0 |
WEIGHT INCREASED | 1/50 (2%) | 1 | 3/92 (3.3%) | 3 | 3/43 (7%) | 3 |
Nervous system disorders | ||||||
AKATHISIA | 4/50 (8%) | 6 | 6/92 (6.5%) | 7 | 3/43 (7%) | 5 |
DIZZINESS | 3/50 (6%) | 3 | 2/92 (2.2%) | 4 | 1/43 (2.3%) | 1 |
HEADACHE | 9/50 (18%) | 17 | 10/92 (10.9%) | 13 | 7/43 (16.3%) | 8 |
PARKINSONISM | 3/50 (6%) | 3 | 10/92 (10.9%) | 14 | 3/43 (7%) | 7 |
SOMNOLENCE | 5/50 (10%) | 5 | 4/92 (4.3%) | 6 | 1/43 (2.3%) | 1 |
TREMOR | 2/50 (4%) | 3 | 3/92 (3.3%) | 3 | 4/43 (9.3%) | 6 |
Psychiatric disorders | ||||||
AGITATION | 1/50 (2%) | 2 | 7/92 (7.6%) | 8 | 2/43 (4.7%) | 3 |
ANXIETY | 3/50 (6%) | 6 | 7/92 (7.6%) | 12 | 2/43 (4.7%) | 2 |
DEPRESSION | 1/50 (2%) | 2 | 2/92 (2.2%) | 2 | 3/43 (7%) | 3 |
INSOMNIA | 12/50 (24%) | 15 | 17/92 (18.5%) | 34 | 4/43 (9.3%) | 4 |
SCHIZOPHRENIA | 5/50 (10%) | 5 | 9/92 (9.8%) | 11 | 3/43 (7%) | 4 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Except for compelling legal reasons, neither the sponsor nor the investigator will communicate to third parties any result of the clinical trial before the CTR has been released by the sponsor.
Results Point of Contact
Name/Title | Senior Vice President, Global Clinical Development |
---|---|
Organization | Merck Sharp & Dohme Corp |
Phone | |
ClinicalTrialsDisclosure@merck.com |
- P05785
- Hera;
- 41513