Clinical trial NCT00705783: Intramuscular Depot Formulation of Aripiprazole as Maintenance Treatment in Patients With Schizophrenia
Official title: A 52-week, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of an Intramuscular Depot Formulation of Aripiprazole as Maintenance Treatment in Patients With Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Schizophrenia
Keywords: Aripiprazole
Intramuscular (IM) depot
Schizophrenia
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2008-06-26
Enrollment: 843
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the trial was to evaluate the efficacy, safety, and tolerability of an intramuscular depot formulation of aripiprazole as maintenance treatment in patients with schizophrenia.

The trial was designed into 4 treatment phases. Phase 1 was designed to allow for a patient to be converted from their current antipsychotic treatment to oral non-generic aripiprazole monotherapy (oral conversion phase from 4 to 6 weeks). During Phase 2, the patient was stabilized on oral non-generic aripiprazole monotherapy (oral stabilization phase from a minimum of 4 weeks to a maximum of 12 weeks). Once the patient was stabilized in Phase 2, they entered Phase 3, the single-blind intramuscular (IM) depot aripiprazole stabilization phase. The goal of the phase was to stabilize the patient on the IM depot aripiprazole formulation for a minimum of 12 weeks to a maximum of 36 weeks. When the patient was stabilized, they were eligible to be randomized into the double-blind IM depot maintenance phase (Phase 4). During Phase 4, the patient was assessed for exacerbation of psychotic symptoms and/or impending relapse for up to 52 weeks.

Detailed description: This was a randomized, double-blind, placebo-controlled study consisting of a screening phase and 4 treatment phases. Eligibility was determined during a screening phase of 2 to 42 days. Patients receiving oral treatment with an antipsychotic other than non-generic aripiprazole entered Phase 1. Patients with a lapse in aripiprazole or other antipsychotic treatment at the time of study entry ("lapse" defined as \> 3 consecutive days without medication) entered directly into Phase 2. During Phase 1 (oral conversion), patients were 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 (a minimum of 4 weeks and a maximum of 12 weeks in duration), patients were assessed bi-weekly and stabilized on an oral dose of aripiprazole ranging from 10 mg to 30 mg daily. After stability criteria were met in Phase 2, patients entered the single-blind aripiprazole intramuscular (IM) depot stabilization phase, Phase 3. In Phase 3, patients were stabilized on aripiprazole IM depot for 12 consecutive weeks. Once the patient met the stability criteria, they were eligible to be randomized into the double-blind phase, Phase 4. Patients were randomized in a 2:1 ratio (aripiprazole IM depot vs placebo IM depot) stratified by region and last aripiprazole IM depot injection dose level in Phase 3. During Phase 4, patients were assessed for impending relapse/exacerbation of psychotic symptoms. If a patient was identified with impending relapse/exacerbation of psychotic symptoms, they were withdrawn from the trial and given the opportunity to enroll into an open-label aripiprazole IM depot trial, 31-08-248. Patients that completed Phase 4 (up to and including Week 52) had the option to enroll into an open-label aripiprazole IM depot trial, 31-08-248 (NCT00731549).

Eligibility criteria: Inclusion Criteria:

* Subjects who are able to provide written informed consent and/or consent obtained from a legally acceptable representative (as required by the Institutional Review Board/Institutional Ethics Committee \[IRB/IEC\]), 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 Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) criteria and a history of the illness for at least 3 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, or 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 2 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.
* 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 them to undue risk or interfere with study assessments.
* Subjects who are involuntary incarcerated.
* Subjects who have used an investigational agent within 30 days of screening or prior participation in a clinical study with aripiprazole IM depot.
* Subjects with clinically significant abnormalities in laboratory test results, vital signs, or ECG results; and subjects hospitalized for more than 30 days in the 90 days prior to Phase 1.
* Subjects who fail to wash-out from prohibited concomitant medications, including the use of CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers, antipsychotics, antidepressants (including monoamine oxidase inhibitors \[MAOI}), and mood stabilizers during screening and/or Phase 1.

Primary outcomes:
measure: Time to Exacerbation of Psychotic Symptoms/Impending Relapse
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
Secondary outcomes:
measure: Percentage of Patients Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
measure: Percentage of Responders
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
measure: Percentage of Patients Achieving Remission
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
measure: Mean Change From Baseline in the PANSS Total Score
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
measure: Mean Change From Baseline in the Clinical Global Impression - Severity (CGI-S) Score
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
measure: Mean Change From Baseline in the PANSS Positive Subscale Score
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
measure: Mean Change From Baseline in the PANSS Negative Subscale Score
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
measure: Mean Clinical Global Impression-Improvement (CGI-I) Score
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
measure: Time to Discontinuation
timeFrame: Baseline of the depot maintenance phase to the end of the study (Week 52)
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Otsuka Investigational Site
state: Arizona
city: Anaheim
country: United States
facility: Otsuka Investigational Site
state: California
city: National City
country: United States
facility: Otsuka Investigational Site
state: California
city: Oceanside
country: United States
facility: Otsuka Investigational Site
state: California
city: San Diego
country: United States
facility: Otsuka Investigational Site
state: California
city: Santa Ana
country: United States
facility: Otsuka Investigational Site
state: California
city: Highlands Ranch
country: United States
facility: Otsuka Investigational Site
state: Colorado
city: Norwalk
country: United States
facility: Otsuka Investigational Site
state: Connecticut
city: Altamonte Springs
country: United States
facility: Otsuka Investigational Site
state: Florida
city: Bradenton
country: United States
facility: Otsuka Investigational Site
state: Florida
city: Hollywood
country: United States
facility: Otsuka Investigational Site
state: Florida
city: Maitland
country: United States
facility: Otsuka Investigational Site
state: Florida
city: Miami
country: United States
facility: Otsuka Investigational Site
state: Florida
city: North Miami
country: United States
facility: Otsuka Investigational Site
state: Florida
city: Orange City
country: United States
facility: Otsuka Investigational Site
state: Florida
city: Tampa
country: United States
facility: Otsuka Investigational Site
state: Florida
city: Atlanta
country: United States
facility: Otsuka Investigational Site
state: Georgia
city: Hoffman Estates
country: United States
facility: Otsuka Investigational Site
state: Illinois
city: Munster
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facility: Otsuka Investigational Site
state: Indiana
city: Baton Rouge
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facility: Otsuka Investigational Site
state: Louisiana
city: Baton Rouge
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facility: Otsuka Investigational Site
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city: Lake Charles
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facility: Otsuka Investigational Site
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city: New Orleans
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facility: Otsuka Investigational Site
state: Louisiana
city: Columbia
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facility: Otsuka Investigational Site
state: Maryland
city: Flowood
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facility: Otsuka Investigational Site
state: Mississippi
city: St. Louis
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facility: Otsuka Investigational Site
state: Missouri
city: North Platte
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facility: Otsuka Investigational Site
state: Nebraska
city: Albuquerque
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facility: Otsuka Investigational Site
state: New Mexico
city: Buffalo
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facility: Otsuka Investigational Site
state: New York
city: Cedarhurst
country: United States
facility: Otsuka Investigational Site
state: New York
city: Elmsford
country: United States
facility: Otsuka Investigational Site
state: New York
city: Holliswood
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facility: Otsuka Investigational Site
state: New York
city: Jamaica
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facility: Otsuka Investigational Site
state: New York
city: Staten Island
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facility: Otsuka Investigational Site
state: New York
city: Cleveland
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facility: Otsuka Investigational Site
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city: Oklahoma City
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facility: Otsuka Investigational Site
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state: Pennsylvania
city: Memphis
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facility: Otsuka Investigational Site
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facility: Otsuka Investigational Site
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facility: Otsuka Investigational Site
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city: Bellevue
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state: Washington
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facility: Otsuka Investigational Site
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city: Richland
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state: Washington
city: Ciudad Autónoma de Bs. As.
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facility: Otsuka Investigational Site
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city: La Plata
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state: Buenos Aires
city: Lanús Este
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city: Pueyrredón
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facility: Otsuka Investigational Site
state: Cordoba
city: Rosario
country: Argentina
facility: Otsuka Investigational Site
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Otsuka Investigational Site
city: Buenos Aires
country: Argentina
facility: Otsuka Investigational Site
city: Cordoba
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facility: Otsuka Investigational Site
city: Mendoza
country: Argentina
facility: Otsuka Investigational Site
city: Mendoza
country: Argentina
facility: Otsuka Investigational Site
city: Lovech
country: Bulgaria
facility: Otsuka Investigational Site
city: Pleven
country: Bulgaria
facility: Otsuka Investigational Site
city: Plovdiv
country: Bulgaria
facility: Otsuka Investigational Site
city: Radnevo
country: Bulgaria
facility: Otsuka Investigational Site
city: Region of Veliko Tarnovo
country: Bulgaria
facility: Otsuka Investigational Site
city: Rousse
country: Bulgaria
facility: Otsuka Investigational Site
city: Sofia
country: Bulgaria
facility: Otsuka Investigational Site
city: Varna
country: Bulgaria
facility: Otsuka Investigational Site
city: Ahmedabad
country: India
facility: Otsuka Investigational Site
state: Gujarat
city: Bangalore
country: India
facility: Otsuka Investigational Site
state: Karnataka
city: Chennai
country: India
facility: Otsuka Investigational Site
state: Tamil Nadu
city: Kanpur
country: India
facility: Otsuka Investigational Site
city: Mangalore
country: India
facility: Otsuka Investigational Site
city: Pune
country: India
facility: Otsuka Investigational Site
city: Tirupati
country: India
facility: Otsuka Investigational Site
city: Cheras
country: Malaysia
facility: Otsuka Investigational Site
state: Kuala Lumpur
city: Tanjong Rambutan
country: Malaysia
facility: Otsuka Investigational Site
state: Perak
city: Kuala Lumpur
country: Malaysia
facility: Otsuka Investigational Site
state: Wilayah Persekutuan
city: Selangor
country: Malaysia
facility: Otsuka Investigational Site
city: Mexico
country: Mexico
facility: Otsuka Investigational Site
state: DF
city: Guadalajara
country: Mexico
facility: Otsuka Investigational Site
state: Jalisco
city: Monterrey
country: Mexico
facility: Otsuka Investigational Site
state: Nuevo León
city: Culiacan
country: Mexico
facility: Otsuka Investigational Site
state: Sinaloa
city: San Luis Potosí
country: Mexico
facility: Otsuka Investigational Site
city: Bataan
country: Philippines
facility: Otsuka Investigational Site
state: Central Luzon
city: Mandaluyong
country: Philippines
facility: Otsuka Investigational Site
state: NCR
city: Quezon City
country: Philippines
facility: Otsuka Investigational Site
state: NCR
city: Iloilo
country: Philippines
facility: Otsuka Investigational Site
state: Western Visayas
city: Cebu City
country: Philippines
facility: Otsuka Investigational Site
city: Arad
country: Romania
facility: Otsuka Investigational Site
city: Bucuresti
country: Romania
facility: Otsuka Investigational Site
city: Cluj-Napoca
country: Romania
facility: Otsuka Investigational Site
city: Craiova
country: Romania
facility: Otsuka Investigational Site
city: Oradea
country: Romania
facility: Otsuka Investigational Site
city: Pitesti
country: Romania
facility: Otsuka Investigational Site
city: Lipetsk
country: Russian Federation
facility: Otsuka Investigational Site
city: Moscow
country: Russian Federation
facility: Otsuka Investigational Site
city: Moscow
country: Russian Federation
facility: Otsuka Investigational Site
city: Moscow
country: Russian Federation
facility: Otsuka Investigational Site
city: Nizhny Novgorod
country: Russian Federation
facility: Otsuka Investigational Site
city: Nizhny Novgorod
country: Russian Federation
facility: Otsuka Investigational Site
city: Smolensk
country: Russian Federation
facility: Otsuka Investigational Site
city: St. Petersburg
country: Russian Federation
facility: Otsuka Investigational Site
city: St. Petersburg
country: Russian Federation
facility: Otsuka Investigational Site
city: St. Petersburg
country: Russian Federation
facility: Otsuka Investigational Site
city: Belgrade
country: Serbia
facility: Otsuka Investigational Site
city: Kragujevac
country: Serbia
facility: Otsuka Investigational Site
city: Kosice
country: Slovakia
facility: Otsuka Investigational Site
city: Liptovský Mikuláš
country: Slovakia
facility: Otsuka Investigational Site
city: Presov
country: Slovakia
facility: Otsuka Investigational Site
city: Rimavská Sobota
country: Slovakia
facility: Otsuka Investigational Site
city: Svidnik
country: Slovakia
facility: Otsuka Investigational Site
city: Changhua
country: Taiwan
facility: Otsuka Investigational Site
city: Hualien
country: Taiwan
facility: Otsuka Investigational Site
city: Tainan
country: Taiwan
facility: Otsuka Investigational Site
city: Taipei
country: Taiwan
facility: Otsuka Investigational Site
city: Taipei
country: Taiwan
facility: Otsuka Investigational Site
Study officials:
affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.
name: Raymond Sanchez, MD
role: STUDY_DIRECTOR
References:
citation: Kane JM, Sanchez R, Perry PP, Jin N, Johnson BR, Forbes RA, McQuade RD, Carson WH, Fleischhacker WW. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012 May;73(5):617-24. doi: 10.4088/JCP.11m07530.
citation: Kane JM, Sanchez R, Baker RA, Eramo A, Peters-Strickland T, Perry PP, Johnson BR, Tsai LF, Carson WH, McQuade RD, Fleischhacker WW. Patient-Centered Outcomes with Aripiprazole Once-Monthly for Maintenance Treatment in Patients with Schizophrenia: Results From Two Multicenter, Randomized, Double-Blind Studies. Clin Schizophr Relat Psychoses. 2015 Summer;9(2):79-87. doi: 10.3371/CSRP.KASA.022015. Epub 2015 Feb 24.
citation: Fleischhacker WW, Sanchez R, Johnson B, Jin N, Forbes RA, McQuade R, Baker RA, Carson W, Kane JM. Long-term safety and tolerability of aripiprazole once-monthly in maintenance treatment of patients with schizophrenia. Int Clin Psychopharmacol. 2013 Jul;28(4):171-6. doi: 10.1097/YIC.0b013e3283615dba.