Phase II/III Study of FK949E: Placebo-controlled, Double-blind, Parallel-group Comparative Study and Open-label, Non-controlled Extension Study in Bipolar Disorder Patients With Major Depressive Episodes
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Astellas Pharma Inc
- Enrollment
- 431
- Locations
- 98
- Primary Endpoint
- Change From Baseline to End of Treatment Period I in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 20 Years to 64 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
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.
Intervention: Placebo (Drug)
FK949E 150 mg
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.
Intervention: FK949E (Drug)
FK949E 300 mg
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.
Intervention: FK949E (Drug)
Placebo / 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.
Intervention: FK949E (Drug)
Placebo / 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.
Intervention: Placebo (Drug)
FK949E 150 mg / 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.
Intervention: FK949E (Drug)
FK949E 300 mg / 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.
Intervention: FK949E (Drug)
Outcomes
Primary Outcomes
Change From Baseline to End of Treatment Period I in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
Time Frame: 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 Outcomes
- 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))
- 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))
- 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))
- 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))
- Number of Participants With an Affirmative Response to C-SSRS: Suicidal Behaviors (Treatment Period I)(Weeks 4, 8)
- 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))
- Number of Participants With Adverse Events (Treatment Period I)(Up to 8 weeks)
- 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))
- Change From Baseline in Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS): Total Score (Treatment Period I)(Baseline and Weeks 4, 8)
- 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)
- Number of Participants With MADRS Response (Treatment Period I)(Baseline and Weeks 1, 2, 3, 4, 6, 8)
- 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)
- Number of Participants With MADRS Remission (Treatment Period I)(Weeks 1, 2, 3, 4, 6, 8)
- 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)
- Change From Baseline in Hamilton Depression Rating Scale (HAM-D17) Total Score (Treatment Period I)(Baseline and Weeks 1, 2, 3, 4, 6, 8)
- 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)
- Number of Participants With HAM-D17 Response (Treatment Period I)(Baseline and Weeks 1, 2, 3, 4, 6, 8)
- 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)
- 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)
- 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)
- 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))
- 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)
- Change From Baseline in DIEPSS: Parkinsonism (Treatment Period I)(Baseline and Weeks 4, 8)
- 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)
- Change From Baseline in MADRS Total Score (Treatment Period I)(Baseline and Weeks 1, 2, 3, 4, 6, 8)
- Change From Baseline in CGI-BP-S: Depression (Treatment Period I)(Baseline and Weeks 1, 2, 3, 4, 6, 8)
- 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)
- Change From Baseline in Young Mania Rating Scale (YMRS) (Treatment Period I)(Baseline and Weeks 1, 2, 3, 4, 6, 8)
- 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)
- Number of Participants With an Affirmative Response to Columbia Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation (Treatment Period I)(Weeks 4, 8)
- Change From Baseline in CGI-BP-S: Overall Bipolar Illness (Treatment Period I)(Baseline and Weeks 1, 2, 3, 4, 6, 8)
- 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)
- Clinical Global Impression-Bipolar Disorder-Change (CGI-BP-C): Mania (Treatment Period I)(Weeks 1, 2, 3, 4, 6, 8)
- 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))
- CGI-BP-C: Depression (Treatment Period I)(Weeks 1, 2, 3, 4, 6, 8)
- 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))
- CGI-BP-C: Overall Bipolar Illness (Treatment Period I)(Weeks 1, 2, 3, 4, 6, 8)
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))