A Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose, Parallel-Group Study of Lurasidone Adjunctive to Lithium or Divalproex for the Prevention of Recurrence in Subjects with Bipolar I Disorder

Study ID
STU 012012-058

Cancer Related
No

Healthy Volunteers
No

Study Sites

Contact
Claire Gardner
214-645-6953
claire.gardner@utsouthwestern.edu

Principal Investigator
Edson Brown

Summary

This study consists of an open-label stabilization phase (of up to a maximum of 20 weeks) followed by a 28-week, double-blind, randomized treatment. across both phases lurasidone (20-80 mg/day) and adjunctive mood stabilizer (lithium or divalproex) will be flexibly dosed.

*Screening/Washout*
Subjects will be evaluated for eligibility during a screening/washout period of 3 to14 days (28 days for subjects on fluoxetine). other than lithium or divalproex, subjects will be tapered off psychotropic medications in a manner consistent with labeling recommendations and usual medical practice. Detailed information on permitted and excluded concomitant medications is provided in Section 8.3.

*open-label Phase*
upon meeting entry criteria subjects will begin open-label treatment with lurasidone (20-80 mg/daily) and either lithium or divalproex (if not currently taking one of these mood stabilizers) on the evening of Visit 2 (open-label phase baseline). For subjects previously not on either lithium or divalproex, investigators will determine which mood stabilizer is most appropriate to initiate.

Lurasidone will be dosed as follows: 20 mg/day on Days 1-3, 40 mg/day on Days 4-7, and flexibly (20-80 mg/day) thereafter. Beginning on Day 8, if dose adjustments are necessary, they should occur at weekly intervals and in increments/decrements of one dose level, based on investigator judgment in order to optimize efficacy and tolerability. However, dose reductions for tolerability purposes are permitted to occur more frequently than at weekly intervals and more than one dose level at a time (maximum of two dose levels at a time).

Subjects will remain in this open-label phase (for a maximum of 20 weeks) until they achieve and maintain clinical stability, defined as total scores [LessThanorequalTo] 12 on the Young Mania Rating Scale (YMRS) and Montgomery-asberg Depression Rating Scale (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.

*Double-blind Phase*
Subjects who achieve clinical stability during the open-label phase will be randomly assigned at double-blind phase baseline (1:1) to lurasidone or matching placebo for up to 28 weeks. Subjects will continue on the mood stabilizer (lithium or divalproex) they were on during the open-label phase.

For subjects randomized to lurasidone, the last open-label dose level will be maintained entering the double-blind phase (Visit 13). For subjects randomized to matching placebo, lurasidone will be discontinued. Subsequent dose adjustments, if necessary, should occur at weekly intervals and in increments/decrements of one dose level, based on investigator judgment.

Stratified randomization will be performed at double-blind phase baseline using an interactive Voice Response System (iVRS) to ensure balance across the two groups relative to mood stabilizer treatment (lithium or divalproex).

Subjects who complete the double-blind phase of the study will be eligible to participate in a separate 3-month, open-label lurasidone extension study.

Subjects experiencing a mood event (see primary efficacy endpoint) will be discontinued and have the option to enroll in the separate 3-month, open-label lurasidone extension study.


*Follow-up*
all subjects who complete the study and those who discontinue the study early will complete a follow-up visit 7 ((+-) 2) days after the last dose of study medication to assess any post study discontinuation adverse effects. The visit will include the following assessments: vital signs, weight, movement disorder scales (SaS/BaRS/aiMS), concomitant medications, and adverse effects. if the subject is continuing into the extension study, the follow-up visit will not be
required.

after the follow-up visit or upon discontinuation from the study, subjects will be referred for continuation of their care as determined by the investigator.

Participant Eligibility

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 at least 18 years of age, 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 (e.g., 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 baseline visits, 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[Single Quote]s judgment, the subject will adhere to this requirement.

9. Adequate contraception is defined as continuous use of either two barrier methods (e.g., condom and spermicide or diaphragm with spermicide) or a hormonal contraceptive. Acceptable hormonal contraceptives include the following:
a) contraceptive implant (such as Norplant(RegisteredTM)) 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, i.e., 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.