Intervention: Lurasidone
Trial phase: Phase 3
ATC code: N05AE05
SMILES: [H][C@@]12C(=O)N(C[C@@H]3CCCC[C@H]3CN3CCN(c4nsc5ccccc45)CC3)C(=O)[C@]1([H])[C@H]1CC[C@@H]2C1
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 144
Group description: During double blind phase subjects received Lurasidone flexibly dosed 40 or 80 mg once daily
Eligibility criteria:
Inclusion Criteria:

Open Label:

Subject provides written informed consent and is willing and able to comply with the protocol in the opinion of the Investigator.

Subject is ≥ 18 and ≤ 75 years of age, on the day of signing the informed consent.

Subject meets DSM-IV-TR criteria for a primary diagnosis of schizophrenia [including disorganized (295.10), paranoid (295.30), undifferentiated (295.90) subtypes as established by clinical interview (using the DSM-IV-TR as a reference and confirmed using the SCID-CT)]. The duration of the subject's illness whether treated or untreated must be ≥ 1 year.

Subject has had at least one prior episode of psychotic exacerbation as judged by the Investigator in the two years preceding screening.

Subject has a PANSS Total score ≥ 80 with a score ≥ 4 on 1 or more of any PANSS Positive subscale items at screening and open-label baseline (Visit 2).

Subject has a CGI-S score of ≥ 4 at screening and open-label baseline (Visit 2).

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.

Female subject 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.

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®) 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.

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 (FSH) concentrations within postmenopausal range as determined by laboratory analysis) are not required to remain abstinent or use adequate contraception.

Subject is able and agrees to remain off prior antipsychotic medication for the duration of the study.

Subject has had a stable living arrangement at the time of screening and agrees to return to a similar living arrangement after discharge, if hospitalized. This criterion is not meant to exclude subjects who have temporarily left a stable living arrangement (e.g., due to psychosis). Such subjects remain eligible to participate in this protocol. Chronically homeless subjects should not be enrolled.

Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening.

Subject who requires concomitant medication treatment with the following agents may be included if they have been on stable doses (i.e., minor adjustments only) for the specified times: 1) antidepressant agents (except fluvoxamine) and/or mood stabilizers (except carbamazepine or oxcarbazepine) must be stable for at least 30 days prior to open-label baseline, 2) oral hypoglycemics must be stable for at least 30 days prior to screening, 3) antihypertensive agents must be stable for at least 30 days prior to screening, and 4) thyroid hormone replacement must be stable for at least 90 days prior to screening. (Note: CYP3A4 inducers and inhibitors will not be allowed).

Subject is willing and able to comply with the protocol assessments and visits, in the opinion of the study nurse/coordinator and the Investigator.

Double-blind -

Subject must achieve and maintain clinical stability for a total of at least 12 weeks in the open label phase, defined as:

a PANSS Total score ≤ 70, a CGI-S score < 4 and a PANSS item score of ≤ 4 (moderate or less) on all PANSS Positive subscale items over at least 12 weeks with the allowance of two excursions (except during the last 4 weeks of the open-label phase) assessed at weekly study visits:

• An excursion is defined as a PANSS total score up to a maximum of 80 and/or a CGI-S score up to a maximum of 4 and/or a PANSS Positive subscale item score up to a maximum of 5.

a PANSS item score of ≤ 4 (moderate or less) on item G8 (uncooperativeness)
taking a stable dose of lurasidone for the last 4 weeks of the open-label phase.

Exclusion Criteria:

Open Label - Subject has a DSM-IV Axis I or Axis II diagnosis other than schizophrenia that has been the primary focus of treatment within 3 months of screening.

Subject answers "yes" to "Suicidal Ideation" item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) on the C-SSRS assessment at screening (in the past month) or baseline.

Subject has attempted suicide within 3 months prior to the screening phase. Subject currently has a clinically significant medical condition including the following: neurological, metabolic (including Type 1 diabetes), hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorder such as unstable angina, congestive heart failure (uncontrolled), or central nervous system (CNS) infection that would pose a risk to the subject if they were to participate in the study or that might confound the results of the study. Subjects with human immunodeficiency virus (HIV) seropositivity (or history of seropositivity) will be excluded.

Note: Active medical conditions that are minor or well-controlled are not exclusionary if they do not affect risk to the subject or the study results. In cases in which the impact of the condition upon risk to the subject or study results is unclear, the Medical Monitor should be consulted. Any subject with a known cardiovascular disease or condition (even if controlled) must be discussed with the Medical Monitor before being screened.

Subject has evidence of any chronic organic disease of the CNS such as tumors, inflammation, and active seizure disorder, vascular disorder, Parkinson's disease, Alzheimer's disease or other forms of dementia, myasthenia gravis, or other degenerative processes. In addition, subject must not have a history of mental retardation or persistent neurological symptoms attributable to serious head injury. Note: Past history of febrile seizures, drug-induced seizures, or alcohol withdrawal seizures is not exclusionary.

Note: Past history of febrile seizures, drug-induced seizures, or alcohol withdrawal seizures is not exclusionary.

Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically significant impaired hepatic function through clinical and laboratory evaluation.

Note: Subjects with serum alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥ 3 times the upper limit of the reference ranges provided by the central laboratory require retesting. If on retesting, the laboratory value remains ≥ 3 times the upper limit, such subjects will be discussed with the Medical Monitor for enrollment consideration.

Subject has a history of stomach or intestinal surgery or any other condition that could interfere with or is judged by the Investigator to interfere with absorption, distribution, metabolism, or excretion of study drug.

Subject with Type 1 or Type 2 insulin-dependent diabetes.

Subject with newly diagnosed Type 2 diabetes during screening. Subject with Type 2 diabetes is eligible for study inclusion if the following condition is met at screening:

if a subject is currently being treated with oral anti-diabetic medication(s), the dose must have been stable for at least 4 weeks prior to screening. Such medication may be adjusted or discontinued during the study, as clinically indicated.

Subject has any abnormal laboratory parameter at screening that indicates a clinically significant medical condition as determined by the Investigator. Subjects with a fasting blood glucose at screening ≥ 126 mg/dL (7.0 mmol/L) or HbA1c ≥ 7.0% will be excluded.

Note: Subjects with random (non-fasting) blood glucose at screening ≥ 200 mg/dL (11.1 mmol/L) must be retested in a fasted state.

Subject has a prolactin concentration > 100 ng/mL at screening or has a history of pituitary adenoma.

Subject has a history of malignancy < 5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Pituitary tumors of any duration are excluded.

Subject is judged to be resistant to antipsychotic treatment defined as any one of the following:

failure to respond to > 2 marketed antipsychotic agents, given at an adequate dose and for an adequate duration (within the past 2 years)
history of treatment with clozapine for refractory psychosis Subject is unlikely to achieve a stable condition for ≥ 12 weeks during the open-label lurasidone phase based on the totality of evidence from the psychiatric history and/or the current presentation.

Subject is receiving an antipsychotic medication above the maximum recommended (country-specific) dose at or prior to screening and, in the judgment of the Investigator, is unlikely to respond to standard doses of lurasidone.

Subject has received depot antipsychotics unless the last injection was at least one treatment cycle or at least 30 days (whichever is longer) prior to the screening phase.

Subject has received treatment with MAO inhibitors within 14 days prior to the screening phase.

Subject requires treatment with any potent CYP3A4 inhibitors or inducers during the study (see Appendix 3).

Subject has received electroconvulsive therapy treatment within the 3 months prior to screening or is expected to require electroconvulsive therapy (ECT) during the study.

Subject has a history of neuroleptic malignant syndrome. Subject exhibits evidence of severe tardive dyskinesia, severe dystonia, or any other severe movement disorder. Severity will be determined by the Investigator.

Subject has a history of alcohol or substance abuse (DSM-IV-TR criteria) within 3 months prior to screening or alcohol or substance dependence (DSM-IV-TR criteria) within 12 months prior to screening. The only exceptions include caffeine or nicotine abuse/dependence.

Subject tests 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 using this drug during the study. This information will be discussed with the Medical Monitor prior to study enrollment.

Subject had a history or presence of an abnormal electrocardiogram (ECG), which in the Investigator's opinion is clinically significant (Medical Monitor may be consulted to determine clinical significance).

Subject has poor peripheral venous access that will limit the ability to draw blood as judged by the Investigator.

Subject has a history of hypersensitivity to more than 2 distinct chemical classes of drug (e.g., sulfas and penicillins).

Subject was screened or washed out previously more than three times for this study.

Subject is currently participating, or has participated in, a study with an investigational or marketed compound or device within 3 months prior to signing the informed consent, or has participated in 2 or more studies within 12 months prior to signing the informed consent.

Subject is homeless or did not have a stable residence for the 3 months prior to the screening phase.

Subject is unable to cooperate with any study procedures, unlikely to adhere to the study procedures and keep appointments, in the opinion of the Investigator, or was planning to relocate during the study.

Subject requires guardianship under the laws of his/her country.

Double-blind - Subjects who in the Investigator's judgment have not been compliant with study medication during the open-label stabilization phase.