A Study to Evaluate the Efficacy of FK949E in Bipolar Disorder Patients With Major Depressive Episodes

Phase 2

Completed

Conditions: Bipolar Disorder

Interventions: Drug: FK949E
Drug: Placebo

Registration Number: NCT01725308

Lead Sponsor: Astellas Pharma Inc

Brief Summary: In period I, the treatment effect of FK949E was compared with that of placebo in a blind manner in bipolar disorder patients with major depressive episodes. In period II, the long-term safety and efficacy of FK949E was evaluated.

Detailed Description: This study consisted of two parts. In Treatment Period I, FK949E or placebo was administered orally in a blind manner to bipolar disorder patients with major depressive episodes, with the aim of evaluating the superiority of FK949E over placebo and the dose response of two doses of FK949E based on changes in Montgomery-Asberg Depression Rating Scale (MADRS) total score. In Treatment Period II, the long-term safety, efficacy and pharmacokinetics of open-label FK949E was evaluated in patients who completed Treatment Period I. An analysis was performed for data in Treatment Period I and another analysis was done for data in combined Treatment Periods I and II.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 431

Inclusion Criteria

Diagnosis of bipolar I or II disorder as specified in the Diagnostic and Statistical Manual of Mental Disorders Ver. 4 Text Revision (DSM-IV-TR,) with a major depressive episode
The Hamilton Depression Rating Scale (HAM-D17) total score of 20 points or more and HAM-D17 depressed mood score of 2 points or more
Able to participate in the study with understanding of and compliance with subject requirements during the study in the investigator's or subinvestigator's opinion

Exclusion Criteria

Concurrent or previous history of DSM-IV-TR Axis I disorders, except bipolar disorder, within the last 6 months before informed consent
Concurrence of DSM-IV-TR Axis II disorder that is considered to greatly affect patient's current mental status
The Young Mania Rating Scale (YMRS) total score of 13 points or more
Nine or more mood episodes within the last 12 months before informed consent
Lack of response to at least 6-week treatment with at least 2 antidepressants for the current major depressive episode in the investigator's or subinvestigator's opinion
History of abuse or dependence of alcohol or substances other than caffeine and nicotine
Treatment with a depot antipsychotic within the last 42 days before primary registration
Unable to stop taking mood stabilizers (lithium carbonate and/or sodium valproate), lamotrigine, antipsychotics, or antidepressants from 7 days before secondary registration
Unable to stop taking antiepileptics (except lamotrigine and sodium valproate), antianxiety agents, hypnotics, sedatives, psychostimulants, antiparkinsonian agents, cerebral ameliorators, antidementia agents, or anorectics, except those specified as conditionally-allowed concomitant drugs, after primary registration
Electroconvulsive therapy within the last 76 days before primary registration
The current major depressive episode persisting for more than 12 months or less than 4 weeks before informed consent
A possible need of psychotherapy during the study period (unless the therapy has been commenced at least 76 days before primary registration and been maintained on a fixed level at fixed frequency)
Documented or suspected conditions such as renal failure, hepatic failure, serious cardiac disease, hepatitis B, hepatitis C, or acquired immunodeficiency syndrome (AIDS) (or to be a carrier of hepatitis B, hepatitis C, or AIDS)
Concurrence of malignancy or history of cured malignancy within 5 years
Concurrence of uncontrolled hypertension (defined as a systolic blood pressure of 180 mmHg or more, or a diastolic blood pressure of 110 mmHg or more at primary registration) or unstable angina that may worsen with the study or may affect the study results based on the clinical judgment of the investigator or sub-investigator
Concurrence of hypotension (defined as a systolic blood pressure of less than 100 mmHg at primary registration) or orthostatic hypotension
History of transient, idiopathic orthostatic hypotension, with or without pre-syncope symptoms or syncope, or a current condition susceptible to transient hypotension, such as dehydration and decreased blood volume
Concurrent or previous history of cerebrovascular disease or transient ischemic attack (TIA)
Abnormal laboratory or electrocardiographic findings considered clinically significant in the investigator's or subinvestigator's opinion (in reference to grade 3 of the Adverse Drug Reactions Severity Grading Criteria [Notification No. 80 of the Safety Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare dated 29 June 1992])
Participation in another clinical study or post-marketing study within the last 12 weeks before informed consent
History of quetiapine therapy during the current major depressive episode
Pregnant or lactating women

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo / FK949E	Placebo	Participants received placebo administered orally once daily at bedtime for 8 weeks in Treatment Period I. Participants who met the transition criteria continued to Treatment Period II which consisted of a transition period in which participants continued to receive placebo for 4 weeks, followed by a 1-week dose adjustment period, and a treatment period in which participants received either open-label FK949E 150 mg or 300 mg (depending on dose increase or reduction guidelines) administered orally for 39 weeks. Participants underwent a dose-tapering period (1 week) and a follow-up period (1 week) thereafter.
FK949E 300 mg / FK949E	FK949E	After 4 days of up-titration, participants received FK949E 300 mg administered orally once daily at bedtime for 8 weeks in Treatment Period I. Participants who met the transition criteria continued to Treatment Period II which consisted of a transition period in which participants continued to receive FK949E 300 mg for 4 weeks followed by a 1-week dose-adjustment period and a treatment period in which participants received either open-label FK949E 150 mg or 300 mg (depending on dose increase or reduction guidelines) administered orally for 39 weeks. Participants underwent a dose-tapering period (1 week) and a follow-up period (1 week) thereafter.
Placebo	Placebo	Participants who received placebo once daily at bedtime for 8 weeks in Treatment Period I and were evaluated against the transition criteria to transfer to Treatment Period II. If transition criteria were not met, participants underwent to a dose-tapering period (1 week) and a follow-up period (1 week) thereafter. If transition criteria were met, participants went into Treatment Period II.
FK949E 150 mg	FK949E	After 2 days of up-titration, participants who received FK949E 150 mg once daily at bedtime for 8 weeks in Treatment Period I and were evaluated against the transition criteria to transfer to Treatment Period II. If transition criteria were not met, participants underwent to a dose-tapering period (1 week) and a follow-up period (1 week) thereafter. If transition criteria were met, participants went into Treatment Period II.
FK949E 300 mg	FK949E	After 4 days of up-titration, participants who received FK949E 300 mg once daily at bedtime for 8 weeks in Treatment Period I and were evaluated against the transition criteria to transfer to Treatment Period II. If transition criteria were not met, participants underwent to a dose-tapering period (1 week) and a follow-up period (1 week) thereafter. If transition criteria were met, participants went into Treatment Period II.
Placebo / FK949E	FK949E	Participants received placebo administered orally once daily at bedtime for 8 weeks in Treatment Period I. Participants who met the transition criteria continued to Treatment Period II which consisted of a transition period in which participants continued to receive placebo for 4 weeks, followed by a 1-week dose adjustment period, and a treatment period in which participants received either open-label FK949E 150 mg or 300 mg (depending on dose increase or reduction guidelines) administered orally for 39 weeks. Participants underwent a dose-tapering period (1 week) and a follow-up period (1 week) thereafter.
FK949E 150 mg / FK949E	FK949E	After 2 days of up-titration, participants received FK949E 150 mg administered orally once daily at bedtime for 8 weeks in Treatment Period I. Participants who met the transition criteria continued to Treatment Period II which consisted of a transition period in which participants continued to receive FK949E 150 mg for 4 weeks followed by a 1-week dose-adjustment period and a treatment period in which participants received either open-label FK949E 150 mg or 300 mg (depending on dose increase or reduction guidelines) administered orally for 39 weeks. Participants underwent a dose-tapering period (1 week) and a follow-up period (1 week) thereafter.

Primary Outcome Measures

Name	Time	Method
Change From Baseline to End of Treatment Period I in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score	Baseline and Week 8	The MADRS is a 10-item scale to measure the severity of depressive episodes, where each item is rated on a scale from 0 to 6. The MADRS total score ranges from 0 to 60 with lower scores indicating less depressive symptoms.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Ideation - Suicidal Thoughts (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 5 items for suicide ideation (1. Wish to be dead; 2. Suicidal thoughts; 3. Suicidal thoughts with a method (no specific plan or intent to act); 4. Suicidal intent (without a specific plan); 5. Suicidal intent with specific plan. If participants responded with a negative response for questions 1 and 2, the remaining questions are skipped. If question 2 was responded to with a positive response, the remaining questions need to be asked. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Ideation - Suicidal Thoughts With Method (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 5 items for suicide ideation (1. Wish to be dead; 2. Suicidal thoughts; 3. Suicidal thoughts with a method (no specific plan or intent to act); 4. Suicidal intent (without a specific plan); 5. Suicidal intent with specific plan. If participants responded with a negative response for questions 1 and 2, the remaining questions are skipped. If question 2 was responded to with a positive response, the remaining questions need to be asked. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Ideation - Suicidal Intent Without a Plan (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 5 items for suicide ideation (1. Wish to be dead; 2. Suicidal thoughts; 3. Suicidal thoughts with a method (no specific plan or intent to act); 4. Suicidal intent (without a specific plan); 5. Suicidal intent with specific plan. If participants responded with a negative response for questions 1 and 2, the remaining questions are skipped. If question 2 was responded to with a positive response, the remaining questions need to be asked. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Ideation - Suicidal Intent With a Plan (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 5 items for suicide ideation (1. Wish to be dead; 2. Suicidal thoughts; 3. Suicidal thoughts with a method (no specific plan or intent to act); 4. Suicidal intent (without a specific plan); 5. Suicidal intent with specific plan. If participants responded with a negative response for questions 1 and 2, the remaining questions are skipped. If question 2 was responded to with a positive response, the remaining questions need to be asked. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Behaviors (Treatment Period I)	Weeks 4, 8	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 7 items to suicidal behaviors (1. suicide attempt; 2. Self-injury without suicide intent; 3. discontinued suicide attempt; 4. interrupted suicide attempt; 5. preliminary action to suicide; 6. suicidal behavior; 7. completed suicide).
CGI-BP-C: Overall Bipolar Illness (Combined Treatment Period I and II)	Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 1)	The CGI-BP-C is a scale which assesses the degree of change or improvement from baseline for each of overall bipolar illness, depression and mania, by grading it using 8 grades, from 1 (very much improved) to 7 (very much worse) or 8 (not applicable). Grade 8 (not applicable) was regarded as a missing value for purposes of calculating the mean score. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With Adverse Events (Treatment Period I)	Up to 8 weeks	An adverse event (AE) is defined as any undesirable or unintended sign (including abnormal laboratory test values), symptom, or disease occurring while the study drug was administered, regardless of whether or not there was a causal relationship with the study drug. A serious AE is defined as a an event resulting in death, persistent or significant disability/incapacity or congenital anomaly or birth defect, was life-threatening, required or prolonged hospitalization or was considered medically important.
Number of Participants With Adverse Events (Combined Treatment Period I and II)	Up to 54 weeks (Placebo / FK949E, from week 12 to week 52, for FK949E 150 mg / FK949E & FK949E 300 mg / FK949E groups, from week 0 to week 52)	An AE is defined as any undesirable or unintended sign (including abnormal laboratory test values), symptom, or disease occurring while the study drug was administered, regardless of whether or not there was a causal relationship with the study drug. A serious AE is defined as a an event resulting in death, persistent or significant disability/incapacity or congenital anomaly or birth defect, was life-threatening, required or prolonged hospitalization or was considered medically important. AEs reported are AEs that occurred after the start of the FK949E treatment for all groups.
Change From Baseline in Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS): Total Score (Treatment Period I)	Baseline and Weeks 4, 8	The DIEPSS is a scale used to evaluate drug-induced extrapyramidal symptoms. DIEPSS is composed of 8 individual symptom parameters and a global assessment of severity, each rated on a 5-point scale, with lower scores indicating as "normal." The DIEPSS total score ranges from 0 (none, normal) to 32 (severe), and excludes the global assessment of severity.
Change From Baseline in MADRS Total Score (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 1, 2, 3, 4, 6, 8, 10, 12 13, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52	The MADRS is a10-item scale to measure the severity of depressive episodes, where each item is rated on a scale from 0 to 6. The MADRS total score ranges from 0 to 60 with lower scores indicating less depressive symptoms. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Number of Participants With MADRS Response (Treatment Period I)	Baseline and Weeks 1, 2, 3, 4, 6, 8	A MADRS response was defined as a decrease in MADRS total score of 50% or more from baseline. The MADRS is a10-item scale to measure the severity of depressive episodes, where each item is rated on a scale from 0 to 6. The MADRS total score ranges from 0 to 60 with lower scores indicating less depressive symptoms.
Number of Participants With MADRS Response (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52	A MADRS response was defined as a decrease in MADRS total score of 50% or more from baseline. The MADRS is a 10-item scale to measure the severity of depressive episodes, where each item is rated on a scale from 0 to 6. The MADRS total score ranges from 0 to 60 with lower scores indicating less depressive symptoms. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Number of Participants With MADRS Remission (Treatment Period I)	Weeks 1, 2, 3, 4, 6, 8	MADRS remission was defined as MADRS total score of 12 or less. The MADRS is a 10-item scale to measure the severity of depressive episodes, where each item is rated on a scale from 0 to 6. The MADRS total score ranges from 0 to 60 with lower scores indicating less depressive symptoms.
Number of Participants With MADRS Remission (Combined Treatment Period I and II)	Weeks 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52	MADRS remission was defined as MADRS total score of 12 or less. The MADRS is a 10-item scale to measure the severity of depressive episodes, where each item is rated on a scale from 0 to 6. The MADRS total score ranges from 0 to 60 with lower scores indicating less depressive symptoms. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Change From Baseline in Hamilton Depression Rating Scale (HAM-D17) Total Score (Treatment Period I)	Baseline and Weeks 1, 2, 3, 4, 6, 8	The HAM-D17 is a clinician-rated 17-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score ranges from 0 to 52, where a higher score indicates a greater depressive state.
Change From Baseline in HAM-D17 (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 28, 36, 40, 44, 52	The HAM-D17 is a clinician-rated 17-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score ranges from 0 to 52, where a higher score indicates a greater depressive state. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Number of Participants With HAM-D17 Response (Treatment Period I)	Baseline and Weeks 1, 2, 3, 4, 6, 8	A HAM-D17 response was defined as a decrease in HAM-D17 total score of 50% or more from baseline. The HAM-D17 is a clinician-rated 17-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score ranges from 0 to 52, where a higher score indicates a greater depressive state.
Number of Participants With HAM-D17 Response (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 28, 36, 44, 52	A HAM-D17 response was defined as a decrease in HAM-D17 total score of 50% or more from baseline. The HAM-D17 is a clinician-rated 17-item scale for assessing the severity of depression symptoms. The scores for each item range from 0 to 4 or 0 to 2, where 0 represents no symptoms. The rating is based on the past 7 days prior to the time of assessment. The total score ranges from 0 to 52, where a higher score indicates a greater depressive state. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Change From Baseline in Clinical Global Impression-Bipolar Disorder-Severity (CGI-BP-S): Mania (Treatment Period I)	Baseline and Weeks 1, 2, 3, 4, 6, 8	The CGI-BP-S is a scale which assesses a participant's severity of their overall bipolar illness, depression, and mania as assessed by the clinician using a scale from 1 (not ill) to 7 (very severely ill).
Change From Baseline in CGI-BP-S: Mania (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52	The CGI-BP-S is a scale which assesses a participant's severity of their overall bipolar illness, depression, and mania as assessed by the clinician using a scale from 1 (not ill) to 7 (very severely ill). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Behaviors - Suicide Attempt (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 7 items to suicidal behaviors (1. suicide attempt; 2. Self-injury without suicide intent; 3. discontinued suicide attempt; 4. interrupted suicide attempt; 5. preliminary action to suicide; 6. suicidal behavior; 7. completed suicide). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Change From Baseline in DIEPSS: Total Score (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 4, 8, 12, 16, 20, 28, 36, 44, 52	The DIEPSS is a scale used to evaluate drug-induced extrapyramidal symptoms. DIEPSS is composed of 8 individual symptom parameters and a global assessment of severity, each rated on a 5-point scale, with lower scores indicating as "normal." The DIEPSS total score ranges from 0 (none, normal) to 32 (severe), and excludes the global assessment of severity. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Change From Baseline in DIEPSS: Parkinsonism (Treatment Period I)	Baseline and Weeks 4, 8	The DIEPSS is a scale used to evaluate drug-induced extrapyramidal symptoms. DIEPSS is composed of 8 individual symptom parameters and a global assessment of severity, each rated on a 5-point scale, with lower scores indicating as "normal." Parkinsonism is a total of the gait disturbance, bradykinesia, salivation, muscle rigidity, and tremor scores and ranges from 0 (none, normal) to 20 (severe).
Change From Baseline in DIEPSS: Parkinsonism (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 4, 8, 12, 16, 20, 28, 36, 44, 52	The DIEPSS is a scale used to evaluate drug-induced extrapyramidal symptoms. DIEPSS is composed of 8 individual symptom parameters and a global assessment of severity, each rated on a 5-point scale, with lower scores indicating as "normal." Parkinsonism is a total of the gait disturbance, bradykinesia, salivation, muscle rigidity, and tremor scores and ranges from 0 (none, normal) to 20 (severe). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Change From Baseline in MADRS Total Score (Treatment Period I)	Baseline and Weeks 1, 2, 3, 4, 6, 8	The MADRS is a 10-item scale to measure the severity of depressive episodes, where each item is rated on a scale from 0 to 6. The MADRS total score ranges from 0 to 60 with lower scores indicating less depressive symptoms.
Change From Baseline in CGI-BP-S: Depression (Treatment Period I)	Baseline and Weeks 1, 2, 3, 4, 6, 8	The CGI-BP-S is a scale which assesses a participant's severity of their overall bipolar illness, depression, and mania as assessed by the clinician with the scale from 1 (not ill) to 7 (very severely ill).
Change From Baseline in CGI-BP-S: Depression (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52	The CGI-BP-S is a scale which assesses a participant's severity of their overall bipolar illness, depression, and mania as assessed by the clinician using a scale from 1 (not ill) to 7 (very severely ill). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Change From Baseline in Young Mania Rating Scale (YMRS) (Treatment Period I)	Baseline and Weeks 1, 2, 3, 4, 6, 8	The YMRS is a scale used to evaluate manic symptoms. The YMRS total score was the total assessment of assessed points for 11 items, ranges from 0 to 60 (each item is scored from either 0-4 or 0-8 by severity (0 = absent and 4/8 = displays mood/behavior to a greater degree). A lower score indicates "Absent" or "Normal."
Change From Baseline in YMRS (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52	The YMRS is a scale used to evaluate manic symptoms. The YMRS total score was the total assessment of assessed points for 11 items, ranges from 0 to 60 (each item is scored from either 0-4 or 0-8 by severity (0 = absent and 4/8 = displays mood/behavior to a greater degree). A lower score indicates "Absent" or "Normal." Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Number of Participants With an Affirmative Response to Columbia Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation (Treatment Period I)	Weeks 4, 8	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 5 items for suicide ideation (1. Wish to be dead; 2. Suicidal thoughts; 3. Suicidal thoughts with a method (no specific plan or intent to act); 4. Suicidal intent (without a specific plan); 5. Suicidal intent with specific plan. If participants responded with a negative response for questions 1 and 2, the remaining questions are skipped. If question 2 was responded to with a positive response, the remaining questions need to be asked.
Change From Baseline in CGI-BP-S: Overall Bipolar Illness (Treatment Period I)	Baseline and Weeks 1, 2, 3, 4, 6, 8	The CGI-BP-S is a scale which assesses a participant's severity of their overall bipolar illness, depression, and mania as assessed by the clinician with the scale from 1 (not ill) to 7 (very severely ill).
Change From Baseline in CGI-BP-S: Overall Bipolar Illness (Combined Treatment Period I and II)	Baseline (Week 0 for FK949E 150 mg/FK949E & FK949E 300 mg/FK949E and Week 12 for Placebo/FK949E) and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52	The CGI-BP-S is a scale which assesses a participant's severity of their overall bipolar illness, depression, and mania as assessed by the clinician using a scale from 1 (not ill) to 7 (very severely ill). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-12.
Clinical Global Impression-Bipolar Disorder-Change (CGI-BP-C): Mania (Treatment Period I)	Weeks 1, 2, 3, 4, 6, 8	The CGI-BP-C is a scale which assesses the degree of change or improvement from baseline for each of overall bipolar illness, depression and mania, by grading it using 8 grades, from 1 (very much improved) to 7 (very much worse) or 8 (not applicable). Grade 8 (not applicable) was regarded as a missing value for purposes of calculating the mean score.
CGI-BP-C: Mania (Combined Treatment Period I and II)	Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 1)	The CGI-BP-C is a scale which assesses the degree of change or improvement from baseline for each of overall bipolar illness, depression and mania, by grading it using 8 grades, from 1 (very much improved) to 7 (very much worse) or 8 (not applicable). Grade 8 (not applicable) was regarded as a missing value for purposes of calculating the mean score. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
CGI-BP-C: Depression (Treatment Period I)	Weeks 1, 2, 3, 4, 6, 8	The CGI-BP-C is a scale which assesses the degree of change or improvement from baseline for each of overall bipolar illness, depression and mania, by grading it using 8 grades, from 1 (very much improved) to 7 (very much worse) or 8 (not applicable). Grade 8 (not applicable) was regarded as a missing value for purposes of calculating the mean score.
CGI-BP-C: Depression (Combined Treatment Period I and II)	Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 1)	The CGI-BP-C is a scale which assesses the degree of change or improvement from baseline for each of overall bipolar illness, depression and mania, by grading it using 8 grades, from 1 (very much improved) to 7 (very much worse) or 8 (not applicable). Grade 8 (not applicable) was regarded as a missing value for purposes of calculating the mean score. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
CGI-BP-C: Overall Bipolar Illness (Treatment Period I)	Weeks 1, 2, 3, 4, 6, 8	The CGI-BP-C is a scale which assesses the degree of change or improvement from baseline for each of overall bipolar illness, depression and mania, by grading it using 8 grades, from 1 (very much improved) to 7 (very much worse) or 8 (not applicable). Grade 8 (not applicable) was regarded as a missing value for purposes of calculating the mean score.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Ideation - Wish to be Dead (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 5 items for suicide ideation (1. Wish to be dead; 2. Suicidal thoughts; 3. Suicidal thoughts with a method (no specific plan or intent to act); 4. Suicidal intent (without a specific plan); 5. Suicidal intent with specific plan. If participants responded with a negative response for questions 1 and 2, the remaining questions are skipped. If question 2 was responded to with a positive response, the remaining questions need to be asked. Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Behaviors - Self-injury Behavior Without Intent (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 7 items to suicidal behaviors (1. suicide attempt; 2. Self-injury without suicide intent; 3. discontinued suicide attempt; 4. interrupted suicide attempt; 5. preliminary action to suicide; 6. suicidal behavior; 7. completed suicide). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Behaviors - Discontinued Attempt (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 7 items to suicidal behaviors (1. suicide attempt; 2. Self-injury without suicide intent; 3. discontinued suicide attempt; 4. interrupted suicide attempt; 5. preliminary action to suicide; 6. suicidal behavior; 7. completed suicide). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Behaviors - Interrupted Attempt (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 7 items to suicidal behaviors (1. suicide attempt; 2. Self-injury without suicide intent; 3. discontinued suicide attempt; 4. interrupted suicide attempt; 5. preliminary action to suicide; 6. suicidal behavior; 7. completed suicide). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Behaviors - Preliminary Act to Suicide (Combined Treatment Period I and II	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 7 items to suicidal behaviors (1. suicide attempt; 2. Self-injury without suicide intent; 3. discontinued suicide attempt; 4. interrupted suicide attempt; 5. preliminary action to suicide; 6. suicidal behavior; 7. completed suicide). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Behaviors - Suicidal Behavior (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 7 items to suicidal behaviors (1. suicide attempt; 2. Self-injury without suicide intent; 3. discontinued suicide attempt; 4. interrupted suicide attempt; 5. preliminary action to suicide; 6. suicidal behavior; 7. completed suicide). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10
Number of Participants With an Affirmative Response to C-SSRS: Suicidal Behaviors - Completed Suicide (Combined Treatment Period I and II)	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (Placebo/FK949E only from week 12, FK949E 150 mg/FK949E & FK949E 300 mg/FK949E from week 4)	The C-SSRS is a scale for assessing risk for suicidal behavior and suicide ideation and was administered by the clinician. Affirmative or negative responses were provided to 7 items to suicidal behaviors (1. suicide attempt; 2. Self-injury without suicide intent; 3. discontinued suicide attempt; 4. interrupted suicide attempt; 5. preliminary action to suicide; 6. suicidal behavior; 7. completed suicide). Baseline for Placebo / FK949E was at week 12 therefore no data were calculated for weeks 1-10.

Trial Locations

Locations (98): Site JP00009
🇯🇵
Chiba, Japan
Site JP00037
🇯🇵
Fukuoka, Japan
Site JP00038
🇯🇵
Fukuoka, Japan
Site JP00040
🇯🇵
Fukuoka, Japan
Site JP00083
🇯🇵
Fukuoka, Japan
Site JP00094
🇯🇵
Fukuoka, Japan
Site JP00095
🇯🇵
Fukuoka, Japan
Site JP00006
🇯🇵
Gunma, Japan
Site JP00039
🇯🇵
Fukuoka, Japan
Site JP00041
🇯🇵
Fukuoka, Japan
Site JP00082
🇯🇵
Fukuoka, Japan
Site JP00091
🇯🇵
Fukuoka, Japan
Site JP00059
🇯🇵
Hokkaido, Japan
Site JP00061
🇯🇵
Hokkaido, Japan
Site JP00074
🇯🇵
Hokkaido, Japan
Site JP00021
🇯🇵
Kanagawa, Japan
Site JP00023
🇯🇵
Kanagawa, Japan
Site JP00025
🇯🇵
Kanagawa, Japan
Site JP00042
🇯🇵
Kumamoto, Japan
Site JP00032
🇯🇵
Kyoto, Japan
Site JP00029
🇯🇵
Shizuoka, Japan
Site JP00012
🇯🇵
Tokyo, Japan
Site JP00013
🇯🇵
Tokyo, Japan
Site JP00045
🇯🇵
Tokyo, Japan
Site JP00071
🇯🇵
Tokyo, Japan
Site JP00090
🇯🇵
Tokyo, Japan
Site JP00099
🇯🇵
Tokyo, Japan
Site JP00044
🇯🇵
Tottori, Japan
Site JP00003
🇯🇵
Akita, Japan
Site JP00030
🇯🇵
Aichi, Japan
Site JP00031
🇯🇵
Aichi, Japan
Site JP00052
🇯🇵
Aichi, Japan
Site JP00055
🇯🇵
Aichi, Japan
Site JP00072
🇯🇵
Aichi, Japan
Site JP00092
🇯🇵
Aichi, Japan
Site JP00008
🇯🇵
Chiba, Japan
Site JP00002
🇯🇵
Fukuoka, Japan
Site JP00058
🇯🇵
Fukuoka, Japan
Site JP00096
🇯🇵
Fukuoka, Japan
Site JP00098
🇯🇵
Fukuoka, Japan
Site JP00004
🇯🇵
Fukushima, Japan
Site JP00097
🇯🇵
Fukuoka, Japan
Site JP00007
🇯🇵
Gunma, Japan
Site JP00028
🇯🇵
Gifu, Japan
Site JP00035
🇯🇵
Hiroshima, Japan
Site JP00067
🇯🇵
Hiroshima, Japan
Site JP00001
🇯🇵
Hokkaido, Japan
Site JP00068
🇯🇵
Hokkaido, Japan
Site JP00073
🇯🇵
Hokkaido, Japan
Site JP00056
🇯🇵
Hiroshima, Japan
Site JP00062
🇯🇵
Hokkaido, Japan
Site JP00069
🇯🇵
Hokkaido, Japan
Site JP00076
🇯🇵
Hokkaido, Japan
Site JP00050
🇯🇵
Kumamoto, Japan
Site JP00005
🇯🇵
Ibaraki, Japan
Site JP00049
🇯🇵
Kagawa, Japan
Site JP00084
🇯🇵
Kyoto, Japan
Site JP00075
🇯🇵
Nara, Japan
Site JP00077
🇯🇵
Miyagi, Japan
Site JP00027
🇯🇵
Nagano, Japan
Site JP00043
🇯🇵
Okinawa, Japan
Site JP00034
🇯🇵
Osaka, Japan
Site JP00063
🇯🇵
Osaka, Japan
Site JP00053
🇯🇵
Oita, Japan
Site JP00054
🇯🇵
Okayama, Japan
Site JP00079
🇯🇵
Okayama, Japan
Site JP00046
🇯🇵
Okinawa, Japan
Site JP00033
🇯🇵
Osaka, Japan
Site JP00047
🇯🇵
Osaka, Japan
Site JP00036
🇯🇵
Tokushima, Japan
Site JP00010
🇯🇵
Tokyo, Japan
Site JP00011
🇯🇵
Tokyo, Japan
Site JP00018
🇯🇵
Tokyo, Japan
Site JP00014
🇯🇵
Tokyo, Japan
Site JP00048
🇯🇵
Tokyo, Japan
Site JP00015
🇯🇵
Tokyo, Japan
Site JP00016
🇯🇵
Tokyo, Japan
Site JP00017
🇯🇵
Tokyo, Japan
Site JP00019
🇯🇵
Tokyo, Japan
Site JP00057
🇯🇵
Tokyo, Japan
Site JP00020
🇯🇵
Tokyo, Japan
Site JP00051
🇯🇵
Tokyo, Japan
Site JP00066
🇯🇵
Tokyo, Japan
Site JP00070
🇯🇵
Tokyo, Japan
Site JP00078
🇯🇵
Tokyo, Japan
Site JP00060
🇯🇵
Tokyo, Japan
Site JP00064
🇯🇵
Tokyo, Japan
Site JP00085
🇯🇵
Tokyo, Japan
Site JP00065
🇯🇵
Tokyo, Japan
Site JP00081
🇯🇵
Tokyo, Japan
Site JP00086
🇯🇵
Tokyo, Japan
Site JP00087
🇯🇵
Tokyo, Japan
Site JP00089
🇯🇵
Tokyo, Japan
Site JP00093
🇯🇵
Tokyo, Japan
Site JP00026
🇯🇵
Toyama, Japan
Site JP00024
🇯🇵
Kanagawa, Japan
Site JP00022
🇯🇵
Kanagawa, Japan
Site JP00088
🇯🇵
Tokyo, Japan