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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00705783
Recruitment Status : Completed
First Posted : June 26, 2008
Results First Posted : July 19, 2013
Last Update Posted : July 19, 2013
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

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.


Condition or disease Intervention/treatment Phase
Schizophrenia Drug: Aripiprazole depot Drug: Placebo depot Phase 3

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 843 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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 Start Date : July 2008
Actual Primary Completion Date : August 2010
Actual Study Completion Date : February 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: Aripiprazole depot
Patients received aripiprazole 300 mg or 400 mg depot intramuscularly every 28 days for 52 weeks.
Drug: Aripiprazole depot
Aripiprazole depot was supplied in 400 mg lyophilized vials. Patients received aripiprazole 300 mg if they were unable to tolerate aripiprazole 400 mg.
Other Name: Abilify

Placebo Comparator: Placebo depot
Patients received placebo intramuscularly every 28 days for 52 weeks.
Drug: Placebo depot
Placebo depot was supplied in 400 mg lyophilized vials.




Primary Outcome Measures :
  1. Time to Exacerbation of Psychotic Symptoms/Impending Relapse [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    A patient experienced an exacerbation of psychotic symptoms/impending relapse if they met any of the following 4 criteria. 1) Clinical Global Impression of Improvement score ≥ 5 and either an increase on any of the following Positive and Negative Syndrome Scale (PANSS) items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score > 4 with an increase of ≥ 2 on that item since randomization or an increase on any of the same PANSS items to a score > 4 and an increase of ≥ 4 on the same combined PANSS items since randomization, 2) Hospitalization due to worsening of psychotic symptoms, 3) Clinical Global Impression of Severity of Suicide (CGI-SS) score of 4 or 5 on Part 1 and/or 6 or 7 on Part 2, or 4) Violent behavior resulting in clinically significant self-injury, injury to another person, or property damage.


Secondary Outcome Measures :
  1. Percentage of Patients Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    This is the key secondary Outcome Measure.

  2. Percentage of Responders [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    A patient was considered to be a responder if all of the following criteria were met. 1) Outpatient status, 2) PANSS total score ≤ 80, 3) Lack of specific psychotic symptoms on the PANSS as measured by a score of ≤ 4 on each of the following items (possible scores of 1 to 7 for each item): Conceptual disorganization, suspiciousness, hallucinatory behavior, unusual thought content, and 4) Clinical Global Impression of Severity of Illness (CGI-S) ≤ 4 (moderately ill) and 5) CGI-SS ≤ 2 (mildly suicidal) on Part 1 and ≤ 5 (minimally worsened) on Part 2.

  3. Percentage of Patients Achieving Remission [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    A patient was considered to have achieved remission if they had a score of ≤ 3 on each of the following PANSS items, maintained for a period of 6 months: Delusions (P1), unusual thought content (G9), hallucinatory behavior (P3), conceptual disorganization (P2), mannerisms/posturing (G5), blunted affect (N1), social withdrawal (N4), and lack of spontaneity (N6).

  4. Mean Change From Baseline in the PANSS Total Score [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    The PANSS consists of 3 subscales (Positive Subscale, 7 constructs, scores ranged from 7-49, Negative Subscale, 7 constructs, scores ranged from 7-49, General Psychopathology Subscale, 16 constructs, scores ranged from 16-112) containing a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. The PANSS total score ranged from 30-210 with a higher score indicating more severe symptoms. A negative change score indicates improvement.

  5. Mean Change From Baseline in the Clinical Global Impression - Severity (CGI-S) Score [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    The severity of illness for each patient was rated using the CGI-S. To assess CGI-S, the rater or investigator answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" Response choices included: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients. The CGI-S score ranged from 0-7 with a higher score indicating greater illness. A negative change score indicates improvement.

  6. Mean Change From Baseline in the PANSS Positive Subscale Score [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    The PANSS Positive Subscale consists of 7 symptom constructs (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. Scores on each subscale ranged from 7-49 with a higher score indicating more severe symptoms. A negative change score indicates improvement.

  7. Mean Change From Baseline in the PANSS Negative Subscale Score [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    The PANSS Negative Subscale consists of 7 symptom constructs (blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking). For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. Scores on each subscale ranged from 7-49 with a higher score indicating more severe symptoms. A negative change score indicates improvement.

  8. Mean Clinical Global Impression-Improvement (CGI-I) Score [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    The efficacy of the study medication was rated for each patient using the CGI-I scale. The rater or investigator rated the patient's total improvement whether or not it was due entirely to drug treatment. All responses were compared to the patient's condition at Baseline. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The CGI-I score ranged from 0-7 with a higher score indicating less improvement/worsening.

  9. Time to Discontinuation [ Time Frame: Baseline of the depot maintenance phase to the end of the study (Week 52) ]
    Time to discontinuation was defined as the date of randomization to the date of study discontinuation.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00705783


Locations
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United States, Arizona
Otsuka Investigational Site
Chandler, Arizona, United States, 85226
United States, California
Otsuka Investigational Site
Anaheim, California, United States, 92805
Otsuka Investigational Site
National City, California, United States, 91950
Otsuka Investigational Site
Oceanside, California, United States, 92056
Otsuka Investigational Site
San Diego, California, United States, 92123
Otsuka Investigational Site
Santa Ana, California, United States, 92701
United States, Colorado
Otsuka Investigational Site
Highlands Ranch, Colorado, United States, 80130
United States, Connecticut
Otsuka Investigational Site
Norwalk, Connecticut, United States, 06851
United States, Florida
Otsuka Investigational Site
Altamonte Springs, Florida, United States, 32701
Otsuka Investigational Site
Bradenton, Florida, United States, 34208
Otsuka Investigational Site
Hollywood, Florida, United States, 33021
Otsuka Investigational Site
Maitland, Florida, United States, 32751
Otsuka Investigational Site
Miami, Florida, United States, 33135
Otsuka Investigational Site
North Miami, Florida, United States, 33161
Otsuka Investigational Site
Orange City, Florida, United States, 32763
Otsuka Investigational Site
Tampa, Florida, United States, 33613
United States, Georgia
Otsuka Investigational Site
Atlanta, Georgia, United States, 30328
United States, Illinois
Otsuka Investigational Site
Hoffman Estates, Illinois, United States, 60169
United States, Indiana
Otsuka Investigational Site
Munster, Indiana, United States, 46321
United States, Louisiana
Otsuka Investigational Site
Baton Rouge, Louisiana, United States, 70808
Otsuka Investigational Site
Baton Rouge, Louisiana, United States, 70809
Otsuka Investigational Site
Lake Charles, Louisiana, United States, 70601
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New Orleans, Louisiana, United States, 70115
United States, Maryland
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Columbia, Maryland, United States, 21045
United States, Mississippi
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Flowood, Mississippi, United States, 39232
United States, Missouri
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St. Louis, Missouri, United States, 63118
United States, Nebraska
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North Platte, Nebraska, United States, 69101
United States, New Mexico
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Albuquerque, New Mexico, United States, 87131
United States, New York
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Buffalo, New York, United States, 14215
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Cedarhurst, New York, United States, 11516
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Elmsford, New York, United States, 10523
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Holliswood, New York, United States, 11423
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Jamaica, New York, United States, 11418
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Staten Island, New York, United States, 10305
United States, Ohio
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Cleveland, Ohio, United States, 44109
United States, Oklahoma
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Oklahoma City, Oklahoma, United States, 73103
United States, Pennsylvania
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Philadelphia, Pennsylvania, United States, 19131
United States, Tennessee
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Memphis, Tennessee, United States, 38119
United States, Texas
Otsuka Investigational Site
Austin, Texas, United States, 78754
Otsuka Investigational Site
DeSoto, Texas, United States, 75115
United States, Washington
Otsuka Investigational Site
Bellevue, Washington, United States, 98007
Otsuka Investigational Site
Bothell, Washington, United States, 98011
Otsuka Investigational Site
Richland, Washington, United States, 99354
Argentina
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Ciudad Autónoma de Bs. As., Buenos Aires, Argentina, C1058AAJ
Otsuka Investigational Site
La Plata, Buenos Aires, Argentina, 1900
Otsuka Investigational Site
Lanús Este, Buenos Aires, Argentina, B1834IBR
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Pueyrredón, Cordoba, Argentina, X5004ALB
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Rosario, Santa Fe, Argentina, 2000
Otsuka Investigational Site
Buenos Aires, Argentina, C1405BOA
Otsuka Investigational Site
Buenos Aires, Argentina, C1425AHQ
Otsuka Investigational Site
Cordoba, Argentina, X5009BIN
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Mendoza, Argentina, 5500HYF
Otsuka Investigational Site
Mendoza, Argentina, 5500
Bulgaria
Otsuka Investigational Site
Lovech, Bulgaria, 5500
Otsuka Investigational Site
Pleven, Bulgaria, 5800
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Plovdiv, Bulgaria, 4002
Otsuka Investigational Site
Radnevo, Bulgaria, 6260
Otsuka Investigational Site
Region of Veliko Tarnovo, Bulgaria, 5047
Otsuka Investigational Site
Rousse, Bulgaria, 7000
Otsuka Investigational Site
Sofia, Bulgaria, 1113
Otsuka Investigational Site
Varna, Bulgaria, 9010
India
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Ahmedabad, Gujarat, India, 380006
Otsuka Investigational Site
Bangalore, Karnataka, India, 560010
Otsuka Investigational Site
Chennai, Tamil Nadu, India, 600003
Otsuka Investigational Site
Kanpur, India, 208005
Otsuka Investigational Site
Mangalore, India, 575018
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Pune, India, 411004
Otsuka Investigational Site
Tirupati, India, 517507
Malaysia
Otsuka Investigational Site
Cheras, Kuala Lumpur, Malaysia, 56000
Otsuka Investigational Site
Tanjong Rambutan, Perak, Malaysia, 31250
Otsuka Investigational Site
Kuala Lumpur, Wilayah Persekutuan, Malaysia, 50603
Otsuka Investigational Site
Selangor, Malaysia, 43000
Mexico
Otsuka Investigational Site
Mexico, DF, Mexico, 6700
Otsuka Investigational Site
Guadalajara, Jalisco, Mexico, 44280
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Monterrey, Nuevo León, Mexico, 64040
Otsuka Investigational Site
Culiacan, Sinaloa, Mexico, 80020
Otsuka Investigational Site
San Luis Potosí, Mexico, 78218
Philippines
Otsuka Investigational Site
Bataan, Central Luzon, Philippines, 2105
Otsuka Investigational Site
Mandaluyong, NCR, Philippines, 1553
Otsuka Investigational Site
Quezon City, NCR, Philippines, 1104
Otsuka Investigational Site
Iloilo, Western Visayas, Philippines, 5000
Otsuka Investigational Site
Cebu City, Philippines, 6000
Romania
Otsuka Investigational Site
Arad, Romania, 310022
Otsuka Investigational Site
Bucuresti, Romania, 041914
Otsuka Investigational Site
Cluj-Napoca, Romania, 400012
Otsuka Investigational Site
Craiova, Romania, 200620
Otsuka Investigational Site
Oradea, Romania, 410154
Otsuka Investigational Site
Pitesti, Romania, 110069
Russian Federation
Otsuka Investigational Site
Lipetsk, Russian Federation, 399083
Otsuka Investigational Site
Moscow, Russian Federation, 115409
Otsuka Investigational Site
Moscow, Russian Federation, 115522
Otsuka Investigational Site
Moscow, Russian Federation, 127473
Otsuka Investigational Site
Nizhny Novgorod, Russian Federation, 603107
Otsuka Investigational Site
Nizhny Novgorod, Russian Federation, 603155
Otsuka Investigational Site
Smolensk, Russian Federation, 214019
Otsuka Investigational Site
St. Petersburg, Russian Federation, 188357
Otsuka Investigational Site
St. Petersburg, Russian Federation, 190121
Otsuka Investigational Site
St. Petersburg, Russian Federation, 192019
Serbia
Otsuka Investigational Site
Belgrade, Serbia, 11000
Otsuka Investigational Site
Kragujevac, Serbia, 34000
Slovakia
Otsuka Investigational Site
Kosice, Slovakia, 041 90
Otsuka Investigational Site
Liptovský Mikuláš, Slovakia, 031 23
Otsuka Investigational Site
Presov, Slovakia, 081 81
Otsuka Investigational Site
Rimavská Sobota, Slovakia, 979 12
Otsuka Investigational Site
Svidnik, Slovakia, 089 01
Taiwan
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Changhua, Taiwan, 500
Otsuka Investigational Site
Hualien, Taiwan, 981
Otsuka Investigational Site
Tainan, Taiwan, 704
Otsuka Investigational Site
Taipei, Taiwan, 110
Otsuka Investigational Site
Taipei, Taiwan, 112
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigators
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Study Director: Raymond Sanchez, MD Otsuka Pharmaceutical Development & Commercialization, Inc.

Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT00705783    
Other Study ID Numbers: 31-07-246
First Posted: June 26, 2008    Key Record Dates
Results First Posted: July 19, 2013
Last Update Posted: July 19, 2013
Last Verified: June 2013
Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Aripiprazole
Intramuscular (IM) depot
Schizophrenia
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Aripiprazole
Antidepressive Agents
Psychotropic Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Dopamine Agonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Serotonin 5-HT1 Receptor Agonists
Serotonin Receptor Agonists
Serotonin Agents
Serotonin 5-HT2 Receptor Antagonists
Serotonin Antagonists
Dopamine D2 Receptor Antagonists
Dopamine Antagonists