Bipolar Disorder
Conditions
Keywords
Mood episodes, Bipolar 1 disorder, Intramuscular Injectable, risperidone, safety and efficacy
Brief summary
The purpose of this study is to determine if risperidone is effective and safe in the prevention of mood episodes in patients with bipolar 1 disorder.
Detailed description
RISPERDAL CONSTA (risperidone long-acting injection) may provide substantial improvement, by reducing patient non-compliance, in the long-term treatment of bipolar I disorder. This is a randomized (patients are assigned different treatments based on chance), double-blind, (neither the patient nor the physician knows whether drug or placebo is being taken, or at what dosage) placebo-controlled study to explore the safety and effectiveness of RISPERDAL CONSTA in the prevention of mood episodes in patients with bipolar 1 disorder. This study includes 5 periods: a screening period lasting up to 1 week; an open-label RISPERDAL (oral risperidone) treatment period lasting 3 weeks; an open-label RISPERDAL CONSTA stabilization period lasting 26 weeks; a double-blind period lasting up to 24 months; and an open-label extension with RISPERDAL CONSTA lasting 8 weeks. Efficacy will be assessed using the Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impressions - Severity (CGI-S) scale, Medical Outcomes Study Short Form 36 (SF-36), and the Personal and Social Performance (PSP) scale. Safety will be evaluated throughout the study and includes assessment of adverse events, clinical laboratory tests (including hematology, serum chemistry, blood glucose/lipid profile, prolactin, and urinalysis); electrocardiograms (ECGs), vital signs (pulse and blood pressure), physical examination, body mass index (BMI), and the Extrapyramidal Symptom Rating Scale (ESRS). Oral risperidone (flexible dosage) 1 to 6 mg/day for the first 3 weeks. Risperidone LAI i.m. injections (12.5mg, 25 mg, 37.5 mg, or 50 mg) given every 2 weeks for up to approximately 2.6 years (only 6 months for patients receiving placebo during DB-period)
Interventions
DRUGRisperdal Consta
12.5, 25, 37.5 or 50mg intramuscular (IM) injection every 2 weeks
DRUGPlacebo
Matching placebo intramuscular (IM) injection every 2 weeks
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of bipolar 1 disorder, currently experiencing a mixed or manic episode or stable * Two or more bipolar mood episodes in the last 2 years excluding current episode * Negative pregnancy test
Exclusion criteria
* History of \> than 4 mood episodes a year during the last two years * patients experiencing a depressive episode * History of antisocial or borderline personality illness * Has unstable or serious general medical illness * Has received medications disallowed by study criteria.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had a Mood Relapse. | 24 months | Mood Relapse was defined as: The subject met DSM-IV criteria for a manic, hypomanic, mixed, or depressive episode; or, the subject needed treatment intervention with any mood stabilizer, antipsychotic medication (other than study drug), benzodiazepine (beyond the dosage allowed), or antidepressant medication; or the subject required hospitalization for any bipolar mood episode; or the subject had a YMRS or MADRS score \>12 or a CGI-S score \>4; or a dose increase, or supplementation with oral risperidone or another antipsychotic or mood stabilizer, was needed in the opinion of the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Young Mania Rating Scale (YMRS) Scores. | Baseline and Endpoint (last observation carried forward) of 24 month Double-Blind Period IV | Measure of mania; score range 0 to 60 (lower score = less severity) |
| Change in Montgomery-Åsberg Depression Rating Scale (MADRS) | Baseline and Endpoint (last observation carried forward) of 24 month Double-Blind Period IV | Measure of depression; score range 0 to 60 (lower score = less severity) |
Countries
Austria, India, Malaysia, Poland, Russia, Slovakia, Spain, Taiwan, Ukraine, United States
Participant flow
Recruitment details
A total of 559 (440 + 119) subjects received at least one dose of study drug. A total of 440 subjects (acute episode or stable on other antipsychotic) entered period II, 382 subjects completed and entered period III. An additional 119 subjects (stable on risperidone) entered period III directly. Overall 501 (382 + 119) subjects entered period III.
Pre-assignment details
Subjects with an acute episode or who were stable on another antipsychotic entered Period II; Period II responders entered Period III. Subjects stable on RIS at screening entered Period III directly. Subjects who maintained response and had a stable dose of RIS LAI for the last 8 weeks of Period III were randomized to RIS LAI or placebo(Period IV).
Participants by arm
| Arm | Count |
|---|---|
| RISPERDAL CONSTA risperidone long acting injectable (RIS LAI) 12.5, 25, 37.5 or 50 mg IM injection every 2 weeks | 154 |
| Placebo IM injection every 2 weeks | 149 |
| Total | 303 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period III (Open-Label Stabilization) | Adverse Event | 12 | 0 | 0 |
| Period III (Open-Label Stabilization) | Death | 2 | 0 | 0 |
| Period III (Open-Label Stabilization) | Ineligible to continue trial | 5 | 0 | 0 |
| Period III (Open-Label Stabilization) | Lost to Follow-up | 19 | 0 | 0 |
| Period III (Open-Label Stabilization) | Non responder | 107 | 0 | 0 |
| Period III (Open-Label Stabilization) | Physician Decision | 1 | 0 | 0 |
| Period III (Open-Label Stabilization) | Pregnancy | 2 | 0 | 0 |
| Period III (Open-Label Stabilization) | Subject non-compliant | 1 | 0 | 0 |
| Period III (Open-Label Stabilization) | Withdrawal by Subject | 49 | 0 | 0 |
| Period II (Open-Label Oral Risperidone) | Adverse Event | 0 | 0 | 13 |
| Period II (Open-Label Oral Risperidone) | Death | 0 | 0 | 1 |
| Period II (Open-Label Oral Risperidone) | Ineligible to continue trial | 0 | 0 | 7 |
| Period II (Open-Label Oral Risperidone) | Lost to Follow-up | 0 | 0 | 14 |
| Period II (Open-Label Oral Risperidone) | Non responder | 0 | 0 | 6 |
| Period II (Open-Label Oral Risperidone) | Physician Decision | 0 | 0 | 1 |
| Period II (Open-Label Oral Risperidone) | Withdrawal by Subject | 0 | 0 | 16 |
| Period IV (Double-Blind Treatment) | Adverse Event | 1 | 1 | 0 |
| Period IV (Double-Blind Treatment) | Ineligible to continue the trial | 4 | 4 | 0 |
| Period IV (Double-Blind Treatment) | Lost to Follow-up | 6 | 3 | 0 |
| Period IV (Double-Blind Treatment) | Physician Decision | 10 | 14 | 0 |
| Period IV (Double-Blind Treatment) | Pregnancy | 0 | 2 | 0 |
| Period IV (Double-Blind Treatment) | Subject Non-compliant | 2 | 1 | 0 |
| Period IV (Double-Blind Treatment) | Withdrawal by Subject | 14 | 15 | 0 |
Baseline characteristics
| Characteristic | RISPERDAL CONSTA | Placebo | Total |
|---|---|---|---|
| Age Continuous | 39.1 years STANDARD_DEVIATION 11.81 | 39.2 years STANDARD_DEVIATION 12.4 | 39.2 years STANDARD_DEVIATION 12.08 |
| Sex: Female, Male Female | 79 Participants | 68 Participants | 147 Participants |
| Sex: Female, Male Male | 75 Participants | 81 Participants | 156 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 154 | 24 / 149 | 81 / 440 | 155 / 501 |
| serious Total, serious adverse events | 13 / 154 | 25 / 149 | 8 / 440 | 38 / 501 |
Outcome results
Primary
Number of Participants Who Had a Mood Relapse.
Mood Relapse was defined as: The subject met DSM-IV criteria for a manic, hypomanic, mixed, or depressive episode; or, the subject needed treatment intervention with any mood stabilizer, antipsychotic medication (other than study drug), benzodiazepine (beyond the dosage allowed), or antidepressant medication; or the subject required hospitalization for any bipolar mood episode; or the subject had a YMRS or MADRS score \>12 or a CGI-S score \>4; or a dose increase, or supplementation with oral risperidone or another antipsychotic or mood stabilizer, was needed in the opinion of the investigator.
Time frame: 24 months
Population: Intention to treat. 28 subjects from a Good Clinical Practice noncompliant site and 1 site with alleged research misconduct were excluded from efficacy analyses. The median (interquartile range) for time to relapse (d): Risperdal Consta: NA (173, NA) \& Placebo: 219 (82, NA) \[NA = not available; Risperdal Consta relapse percent \< 50% \& Placebo \<75%\]
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RISPERDAL CONSTA | Number of Participants Who Had a Mood Relapse. | Relapsed | 42 Participants |
| RISPERDAL CONSTA | Number of Participants Who Had a Mood Relapse. | Not Relapsed | 98 Participants |
| Placebo | Number of Participants Who Had a Mood Relapse. | Relapsed | 76 Participants |
| Placebo | Number of Participants Who Had a Mood Relapse. | Not Relapsed | 59 Participants |
p-value: <0.00195% CI: [0.27, 0.59]Log Rank
Secondary
Change in Montgomery-Åsberg Depression Rating Scale (MADRS)
Measure of depression; score range 0 to 60 (lower score = less severity)
Time frame: Baseline and Endpoint (last observation carried forward) of 24 month Double-Blind Period IV
Population: Restricted to subjects with paired baseline and visit endpoint (Period IV) data only. Endpoint is the patient's last nonmissing, postbaseline value in Period IV (last observation carried forward technique)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RISPERDAL CONSTA | Change in Montgomery-Åsberg Depression Rating Scale (MADRS) | 2.8 units on a scale | Standard Deviation 6.66 |
| Placebo | Change in Montgomery-Åsberg Depression Rating Scale (MADRS) | 4.9 units on a scale | Standard Deviation 8.09 |
p-value: 0.0295% CI: [-3.75, -0.32]ANCOVA
Secondary
Change in Young Mania Rating Scale (YMRS) Scores.
Measure of mania; score range 0 to 60 (lower score = less severity)
Time frame: Baseline and Endpoint (last observation carried forward) of 24 month Double-Blind Period IV
Population: Restricted to subjects with paired baseline and visit endpoint (Period IV) data only. Endpoint is the patient's last nonmissing, postbaseline value in Period IV (last observation carried forward technique)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RISPERDAL CONSTA | Change in Young Mania Rating Scale (YMRS) Scores. | 2.9 units on a scale | Standard Deviation 7.34 |
| Placebo | Change in Young Mania Rating Scale (YMRS) Scores. | 9.1 units on a scale | Standard Deviation 10.78 |
p-value: <0.00195% CI: [-8.08, -3.79]ANCOVA