E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bipolar disorder I depression |
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E.1.1.1 | Medical condition in easily understood language |
A mental illness characterized by the occurrence of one or more manic episodes, or mixed episodes. There is also a history of one or more major depressive episodes |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004936 |
E.1.2 | Term | Bipolar depression |
E.1.2 | System Organ Class | 100000004873 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy and safety of lurasidone (in combination with lithium or divalproex) for the maintenance treatment of bipolar I disorder in subjects with or without rapid cycling and/or psychotic features. |
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E.2.2 | Secondary objectives of the trial |
Global severity, assessed by the Clinical Global Impression Bipolar Version, Severity of Illness (CGI-BP-S) score (overall) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Open-label Phase:
1. Subject provides written informed consent and is willing and able to comply with the protocol in the opinion of the Investigator.
2. Subject is 18 to 65 years of age, inclusive, with bipolar I disorder, most recent episode manic, mixed manic, hypomanic, or depressed, with or without rapid cycling disease course (≥ 4 episodes of mood disturbance but < 8 episodes in the previous 12 months), and/or psychotic features (diagnosed by DSM-IV-TR criteria and confirmed by the SCID-CT).
3. Subject has experienced at least one manic, mixed, or depressed episode in the past 2
years. It is strongly recommended that a reliable informant (eg, family member, caregiver, or treating health professional) be available to confirm this history.
4. If currently experiencing a major depressive episode, should be < 12 months in duration.
5. At screening and at open-label baseline, YMRS or MADRS total score ≥ 14 if receiving lithium or divalproex; ≥ 18 if not currently on lithium or divalproex.
6. Subjects not being treated with lithium or divalproex at screening must be willing to initiate lithium or divalproex treatment for the duration of the study.
7. Subject is not pregnant (must have a negative serum pregnancy test at screening) or nursing (must not be lactating) and is not planning pregnancy within the projected duration of the study.
8. Female subject who is of reproductive potential agrees to remain abstinent or use adequate and reliable contraception throughout the study and for at least 30 days after the
last dose of lurasidone has been taken. In the Investigator’s judgment, the subject will adhere to this requirement.
9. Adequate contraception is defined as continuous use of either two barrier methods (eg, condom and spermicide or diaphragm with spermicide) or a hormonal contraceptive. Acceptable hormonal contraceptives include the following: a) contraceptive implant (such as Norplant®) implanted at least 90 days prior to screening; b) injectable contraception (such as medroxyprogesterone acetate injection) given at least 14 days
prior to screening; or c) oral contraception taken as directed for at least 30 days prior to screening.
10. Subjects who are of non-reproductive potential, ie, subject who is surgically sterile, has undergone tubal ligation, or is postmenopausal (defined as at least 12 months of
spontaneous amenorrhea or between 6 and 12 months of spontaneous amenorrhea with follicle stimulating hormone concentrations within postmenopausal range as determined
by laboratory analysis) are not required to remain abstinent or use adequate contraception.
11. Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening.
12. Subject who requires concomitant medication treatment with the following agents may be included if they have been on stable doses for the specified times: 1) oral hypoglycemics
and antihypertensive agents: must be stabilized for at least 30 days prior to screening; 2) thyroid hormone replacement: must be stable for at least 90 days prior to screening.
13. Subject must share a household with another adult or must be in contact with another adult at least 5 days per week. In either condition, the adult will be required to provide consent for the subject’s participation in the trial.
Double-blind Phase:
1. Subjects must achieve consistent clinical stability, defined as total scores ≤ 12 on the YMRS and MADRS over at least 12 weeks, with the allowance of two excursions (YMRS and/or MADRS total scores up to 13 or 14, respectively) except during the last 4 weeks before randomization.
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E.4 | Principal exclusion criteria |
Open-label Phase:
a. Diagnosis of an Axis I or Axis II disorder, other than bipolar I disorder, that is the primary focus of treatment within 3 months of screening
b. Subjects for whom diagnostic agreement between the Investigator and Bracket cannot be reached
c. Ultra-fast rapid cycling (defined as ≥ 8 mood episodes over the previous 12-month period)
d. Subjects who test positive for drugs of abuse at screening. In the event a subject tests positive for cannabinoids (tetrahydrocannabinol), the Investigator will evaluate the subject’s ability to abstain from cannabis during the study
e. Unstable/inadequately treated medical illness
f. The subject answers “yes” to “Suicidal Ideation” items 4 or 5 on the C-SSRS (at time of evaluation)
Double-blind Phase:
a. Subjects who in the Investigator’s judgment have not been compliant with study medication during the stabilization phase
b. Subjects who have not stabilized during the open-label phase (within 20 weeks)
c. Subjects who test positive for drugs of abuse at double-blind phase baseline. In the event a subject tests positive for cannabinoids (tetrahydrocannabinol), the Investigator will evaluate the subject’s ability to abstain from cannabis during the study
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
Time to recurrence of any mood event (from double-blind phase baseline); mood event is defined as any of the following:
- Fulfilled DSM-IV-TR criteria for manic, mixed manic, hypomanic, or depressive episode
- Required treatment intervention for manic, mixed manic, hypomanic, or depressive symptoms with any antipsychotic (other then study drug), antidepressant, mood stabilizer (other than lithium or divalproex), anxiolytic agents, benzodiazepine
(beyond dosage allowed for anxiety, agitation or insomnia)
- Psychiatric hospitalization for any bipolar mood episode
- YMRS or MADRS total score ≥ 18 or CGI-BP-S score ≥ 4 at two consecutive assessments no more than 10 days apart
- Discontinuation from the study because of a mood event (as determined by the Investigator)
Subject meeting criteria for a mood event must be discontinued from the study. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Visit 13-20 (at every visit; visit schedule – every 4 weeks) |
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E.5.2 | Secondary end point(s) |
1. Time to all-cause discontinuation
2. Time to recurrence of a manic, mixed manic, hypomanic, or depressed episode
3. Proportion of subjects who experience a recurrence of a manic, mixed manic, hypomanic, or depressed episode
4. Change from double-blind phase baseline (final visit in the open-label phase) to endpoint in Global severity, assessed by the Clinical Global Impression Bipolar Version, Severity of Illness (CGI-BP-S) scores (overall, depression, mania), YMRS total score, MADRS total score, Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR16) total score, and Positive and Negative Syndrome Scale Positive Subscale (PANSS-P) score
5. Subject self-report of functional impairment associated with symptoms of bipolar disorder, assessed by the Sheehan Disability Scale (SDS) total score and SDS subscales
6. Quality of life assessed by Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)
7. Sleep quality assessed by the Pittsburgh Insomnia Rating Scale (PIRS-2)
8. Health outcome measure: Health Services Utilization Questionnaire (HSUQ) and SF-12 Health Survey
9. Medication Satisfaction Questionnaire (MSQ) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Visit 13-20 (at every visit; visit schedule – every 4 weeks) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Bulgaria |
Chile |
Croatia |
Czech Republic |
France |
Hungary |
India |
Italy |
Poland |
Russian Federation |
Serbia |
Slovakia |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last patient undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |