Intramuscular Depot Formulation of Aripiprazole as Maintenance Treatment in Patients With Schizophrenia (ASPIRE)

• Time to exacerbation of psychotic symptoms/impending relapse from date of randomization in Phase 3 [ Time Frame: 38 weeks ] [ Designated as safety issue: No ]
• Percentage of responders at endpoint in Phase 3 [ Time Frame: 38 weeks ] [ Designated as safety issue: No ]
• Percentage of subjects achieving remission [ Time Frame: 38 weeks ] [ Designated as safety issue: No ]

The purpose of the this trial is to evaluate the efficacy, safety, and tolerability of an intramuscular (IM) depot formulation of aripiprazole as maintenance treatment in patients with schizophrenia

The trial is designed into three treatment phases. Phase 1 is designed to allow for a subject to be converted from the current antipsychotic treatment to oral non-generic aripiprazole monotherapy (oral conversion phase from 4 to 6 weeks). During Phase 2 the subject will be stabilized on oral non-generic aripiprazole monotherapy. Once the subject is stabilized in Phase 2 (oral stabilization phase from minimum 8 weeks to maximum 28 weeks), they are eligible to be randomized into the double-blind IM depot maintenance phase, Phase 3. During Phase 3, the subject will be assessed for exacerbation of psychotic symptoms and impending relapse for up to 38 weeks.

This will be a randomized, double-blind, active-controlled study consisting of a screening phase and three treatment phases. Eligibility will be determined during a screening phase of 2 to 42 days. Subjects currently receiving oral treatment with an antipsychotic other than non-generic aripiprazole will enter Phase 1, and subjects with a lapse in aripiprazole or other antipsychotic treatment at the time of study entry ("lapse" defined as >3 consecutive days without medication) will enter directly into Phase 2.

During Phase 1 (oral conversion), subjects will be cross-titrated during weekly visits from other antipsychotics to oral non-generic aripiprazole monotherapy over a minimum of 4 weeks and a maximum of 6 weeks. During Phase 2 (that will be a minimum of 8 weeks and a maximum of 28 weeks in duration), subjects will be assessed bi-weekly and stabilized on an oral dose of aripiprazole ranging from 10 mg to 30 mg daily. After stability criteria are met at Phase 2, subjects are eligible to be randomized into the double-blind IM depot maintenance phase, Phase 3. Subjects will be randomized with a 2:2:1 (aripiprazole IM depot 400 mg, oral aripiprazole, aripiprazole IM depot 50 mg). During Phase 3 subjects will be assessed for impending relapse/exacerbation of psychotic symptoms. If a subject is identified with impending relapse/exacerbation of psychotic symptoms, they will be withdrawn from the trial and given the opportunity to enroll into an open-label aripiprazole IM depot trial, 31-08-248. Alternatively, subjects that complete Phase 3 (up to and including week-38) will have the option to enroll into an open-label aripiprazole IM depot trial, 31-08-248. Alternatively, subjects that complete Phase 3 (up to and including week-38) will have the option to enroll into an open-label aripiprazole IM depot trial, 31-08-248.

The enrollment figure includes re-screened patients.

• Drug: Intramuscular (IM) Depot Aripiprazole Formulation
  Intramuscular (IM) Depot Aripiprazole Formulation 50 mg or 25 mg, once a month injection
• Drug: Oral Aripiprazole 10 mg - 30 mg, daily
  Oral Aripiprazole 10 mg - 30 mg, daily
• Drug: Intramuscular (IM) Depot Aripiprazole Formulation
  Intramuscular (IM) Depot Aripiprazole Formulation 400 mg or 300 mg, once a month injection

• Active Comparator: 1
  Intramuscular (IM) Depot Aripiprazole Formulation
  Intervention: Drug: Intramuscular (IM) Depot Aripiprazole Formulation
• Active Comparator: 2
  Active Comparator: Oral Aripiprazole
  Intervention: Drug: Oral Aripiprazole 10 mg - 30 mg, daily
• Active Comparator: 3
  Active Comparator: Treatment of Aripiprazole IM Depot
  Intervention: Drug: Intramuscular (IM) Depot Aripiprazole Formulation

Inclusion Criteria:

• Subjects who are able to provide written informed consent and/or consent obtained from a legally acceptable representative (as require by IRB/IEC), prior to the initiation of any protocol-required procedures.
• Male and female subjects 18 to 60 years of age, inclusive, at time of informed consent.
• Subjects with a current diagnosis of schizophrenia as defined by DSM-IV-TR criteria and a history of the illness for at least three years prior to screening.
• Subjects who, in the investigator's judgment, require chronic treatment with an antipsychotic medication.
• Subjects able to understand the nature of the study and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, IM depot injection, discontinuation of prohibited concomitant medications, who can read and understand the written word in order to complete patient-reported outcomes measures, and who can be reliably rated on assessment scales.

Exclusion Criteria:

• Subjects with a current DSM-IV-TR diagnosis other than schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar disorder, delirium, dementia, amnestic or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
• Subjects with schizophrenia that are considered resistant/refractory to antipsychotic treatment by history or response only to clozapine.
• Subjects with a significant risk of violent behavior or a significant risk of committing suicide based on history or investigator's judgment.
• Subjects who currently meet DSM-IV-TR criteria for substance dependence; including alcohol and benzodiazepines, but excluding caffeine and nicotine, or two positive drug screens for cocaine.
• Subjects who are known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones, or hypersensitivity to antipsychotic agents, including aripiprazole..
• Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia at screening.
• Subjects with uncontrolled thyroid function abnormalities.
• Subjects with a history of seizures, neuroleptic malignant syndrome, clinically significant tardive dyskinesia, or other medical condition that would expose the subject to undue risk or interfere with study assessments.
• Subjects who are involuntary incarcerated.
• Subjects who have undergone electroconvulsive therapy within 180 days of entry into Phase 2.
• Subjects who have used an investigational agent within 30 days of screening; and prior participation in a clinical study with aripiprazole IM depot.
• Subjects with clinically significant abnormalities in laboratory test results, vital signs, or ECG results.
• Subjects hospitalized for more than 30 days in the 90 days prior to Phase 1 (or Phase 2 for subjects bypassing Phase 1).
• Subjects requiring more than one benzodiazepine beyond screening (eg, lorazepam and oxazepam).
• Subjects who fail to wash-out from prohibited concomitant medications, including the use of CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers, antipsychotics, antidepressants (including MAOIs), and mood stabilizers, during screening and Phase 1.