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A Multiple Dose Safety, Tolerability and Pharmacokinetics Study in Adult Patients With Schizophrenia Following Administration of Aripiprazole IM Depot

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: NCT01870999
Recruitment Status : Completed
First Posted : June 6, 2013
Results First Posted : January 22, 2014
Last Update Posted : January 22, 2014
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Brief Summary:
This study will evaluate the safety, tolerability, efficacy and pharmacokinetics of aripiprazole intramuscular (IM) depot multiple doses every 4 weeks in adult patients with schizophrenia.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: aripiprazole IM depot Drug: aripiprazole tablets Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Parallel Arm Multiple Dose Tolerability, Pharmacokinetics and Safety Study in Adult Patients With Schizophrenia Following Administration of Aripiprazole IM Depot Formulation Once Every Four Weeks
Study Start Date : November 2007
Actual Primary Completion Date : October 2008
Actual Study Completion Date : October 2008

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: 400 mg Aripiprazole IM Depot
400 mg aripiprazole IM (intramuscular) depot intramuscular injection once every 4 weeks for 5 months. All participants were on a stable dose of 10 mg aripiprazole tablets once daily in the morning for at least 14 days prior to randomization and continued 10 mg aripiprazole tablets once daily on days 1 to 14.
Drug: aripiprazole IM depot
Aripiprazole IM depot supplied as 200 mg or 400 mg vials of lyophilized aripiprazole powder to prepare for IM injection.

Drug: aripiprazole tablets
Aripiprazole tablets 10 mg once daily in the morning for 14 days.

Experimental: 300 mg Aripiprazole IM Depot
300 mg aripiprazole IM depot intramuscular injection once every 4 weeks for 5 months. All participants were on a stable dose of 10 mg aripiprazole tablets once daily in the morning for at least 14 days prior to randomization and continued 10 mg aripiprazole tablets once daily on days 1 to 14.
Drug: aripiprazole IM depot
Aripiprazole IM depot supplied as 200 mg or 400 mg vials of lyophilized aripiprazole powder to prepare for IM injection.

Drug: aripiprazole tablets
Aripiprazole tablets 10 mg once daily in the morning for 14 days.

Experimental: 200 mg Aripiprazole IM depot
200 mg aripiprazole IM depot intramuscular injection once every 4 weeks for 5 months. All participants were on a stable dose of 10 mg aripiprazole tablets once daily in the morning for at least 14 days prior to randomization and continued 10 mg aripiprazole tablets once daily on days 1 to 14.
Drug: aripiprazole IM depot
Aripiprazole IM depot supplied as 200 mg or 400 mg vials of lyophilized aripiprazole powder to prepare for IM injection.

Drug: aripiprazole tablets
Aripiprazole tablets 10 mg once daily in the morning for 14 days.




Primary Outcome Measures :
  1. Number of Participants With Adverse Events as a Measure of Safety [ Time Frame: 7 Months ]
    Safety and tolerability was assessed by the number of participants with adverse events (AE). An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a subject while enrolled in the study, whether or not it was considered drug-related by the investigator. Abnormal laboratory test findings were considered AEs if, in the opinion of the investigator, they represented an abnormal (ie, clinically significant) change from baseline for that individual participant.

  2. Aripiprazole Maximum Steady State Plasma Concentration (Css,Max) [ Time Frame: Pre-dose and 1 to 1344 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for Css,max were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection.

  3. Aripiprazole Minimum Steady State Plasma Concentration (Css,Min) [ Time Frame: 672 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for Css,min were determined directly from the observed data at 672 hours after the fifth monthly injection.

  4. Aripiprazole Area Under the Concentration-time Curve at Steady-state (AUCτ) [ Time Frame: Pre-dose and 1 to 1344 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values of AUCτ were estimated using the linear trapezoidal rule during each dosing interval from 0 to 1344 hours post-dose.


Secondary Outcome Measures :
  1. Aripiprazole Maximum (Peak) Plasma Concentration (Tmax) [ Time Frame: Pre-dose and 1 to 1344 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for tmax were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection.

  2. Aripiprazole Steady-state Plasma Concentration (Css,Avg) [ Time Frame: Pre-dose and 1 to 1344 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for Css,avg were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection.

  3. Aripiprazole Terminal-phase Elimination Half-life (t1/2,z) [ Time Frame: Pre-dose and 1 to 1344 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for aripiprazole. Values for t1/2,z were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection.

  4. Dehydro-aripiprazole Maximum Steady State Plasma Concentration (Css,Max) [ Time Frame: Pre-dose and 1 to 1344 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for dehydro-aripiprazole. Values for Css,max were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection.

  5. Dehydro-aripiprazole Minimum Steady State Plasma Concentration (Css,Min) [ Time Frame: Pre-dose and 1 to 1344 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for dehydro-aripiprazole. Values for Css,min were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection.

  6. Dehydro-aripiprazole Area Under the Concentration-Time Curve at Steady-State (AUCτ) [ Time Frame: Pre-dose and 1 to 1344 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for dehydro-aripiprazole. Values of AUCτ were estimated using the linear trapezoidal rule during each dosing interval from 0 to 1344 hours post-dose.

  7. Dehydro-aripiprazole Maximum (Peak) Plasma Concentration (Tmax) [ Time Frame: Pre-dose and 1 to 1344 hours post-dose at Month 5 ]
    Blood samples were collected for pharmacokinetic parameters pre-dose and 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, 264, 336, 504, 672, 1008 and 1344 hours post-dose and were analyzed for dehydro-aripiprazole. Values for tmax were determined directly from the observed data during the dosing interval (0-1344 hours) after the fifth monthly injection.

  8. Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 12 and Week 24 [ Time Frame: Baseline, Week 12, Week 24 ]
    The PANSS consisted of 3 subscales with a total of 30 symptom constructs each rated on a 7-point scale where 1=absence of symptoms to 7=extremely severe symptoms. The Positive Subscale consisted of 7 positive symptom constructs with a possible subscale score of 7 to 49, the Negative Subscale consisted of 7 negative symptom constructs with a possible subscale score of 7 to 49 and the General Psychopathology Subscale consisted of 16 symptom constructs for a possible subscale score of 16 to 112. The PANSS Total Score ranged from 30 (best) to 210 (worst; indicating more severe symptoms). A Negative change from Baseline indicated improvement.

  9. Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Positive Subscale Scores at Week 12 and Week 24 [ Time Frame: Baseline, Week 12, Week 24 ]
    The PANSS Positive Subscale consisted of 7 symptom constructs: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. Severity was rated on a 7-point scale where 1=absence of symptoms to 7=extremely severe symptoms. The total score on the Positive Subscale ranged from 7 to 49 with a higher score indicating more severe symptoms. A Negative change from Baseline indicated improvement.

  10. Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Negative Subscale Scores at Week 12 and Week 24 [ Time Frame: Baseline, Week 12, Week 24 ]
    The PANSS Negative Subscale consisted of 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. Severity was rated on a 7-point scale where 1=absence of symptoms to 7=extremely severe symptoms. The total score on the Negative Subscale ranged from 7 to 49 with a higher score indicating more severe symptoms. A negative change from Baseline indicated improvement.

  11. Change From Baseline in the Clinical Global Impression- Severity of Illness Score (CGI-S) at Week 12 and Week 24 [ Time Frame: Baseline, Week 12, Week 24 ]
    The severity of illness for each participant was rated using the CGI-S scale. The investigator answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" using an 8-point scale where 0=not assessed to 7=among the most extremely ill patients. A negative change from Baseline indicated improvement.

  12. Clinical Global Impression-Improvement Scale (CGI-I) at Week 12 and Week 24 [ Time Frame: Baseline, Week 12, Week 24 ]
    The participant's overall improvement was rated for each participant using the CGI-I scale. The investigator rated the participant's total improvement by answering the following question: "Compared to his/her condition at baseline (prior to randomization), how much has the patient changed?" using an 8-point scale where 0=not assessed, 1=very much improved to 7=very much worse. Lower scores indicated improvement.

  13. Number of Participants Hospitalized for Adverse Event "Worsening Schizophrenia" [ Time Frame: 7 Months ]
    The number of participants hospitalized for the Adverse Event "Worsening Schizophrenia included all participants who were hospitalized for any Adverse Event pertaining to the exacerbation of schizophrenic symptoms.



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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • diagnosis of schizophrenia as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria
  • good physical health as determined by normal medical history, clinical laboratory results, electrocardiograms (ECGs) and physical examinations
  • ability to provide informed consent and/or consent from a legally acceptable representation
  • body mass index (BMI) of 18 to 35 kg/m^2

Exclusion Criteria:

  • sexually active males and females of child-bearing potential who are not practicing double barrier birth control or are not abstinent during the study plus 30 days for female or 90 days for males following the last dose of medication
  • history of drug or alcohol abuse within 6 months and/or positive urine drug screen
  • participants who consume alcohol beverages routinely
  • participants who consume alcohol beverages during the screening period
  • use of any antipsychotic medication, other prohibited psychotropic medication, and any cytochrome P450 2D6 (CYP2D6) and cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 inducers within 14 days
  • use of any prescription medication unless approved by Medical Monitor or Study Director
  • history of current hepatitis or carrier of HBsAg (Hepatitis B surface antigen) and/or Hepatitis C Virus antibodies (anti-HCV)
  • females who are pregnant or lactating
  • participants who have participated in any clinical trial involving a psychotropic medication within one month prior to enrollment; participants who have participated in a previous IM Depot study within the last 1 year; patients who have previously enrolled and received study medication in an aripiprazole IM Depot clinical trial
  • donation of blood or plasma to a blood bank or in a clinical study (except a screening visit)within 30 days prior to enrollment
  • any major surgery within 30 days prior to enrollment
  • blood transfusion within 30 days prior to enrollment
  • evidence of organ dysfunction or any clinically significant deviation from normal in the physical, electrocardiographic, or clinical laboratory examinations
  • patient represents a significant risk of committing suicide based on history
  • patients currently in an acute relapse
  • patients with Axis I (DSM-IV) diagnosis of schizoaffective or bipolar disorder
  • patients who are considered treatment-resistant to antipsychotic medication
  • patients with a history of neuroleptic malignant syndrome
  • any other sound medical reason as determined by the clinical investigator

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): NCT01870999


Locations
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United States, California
Otsuka Investigative Site
Cerritos, California, United States, 90703
Otsuka Investigative Site
Garden Grove, California, United States, 92845
Otsuka Investigative Site
Glendale, California, United States, 91206
Otsuka Investigative Site
Paramount, California, United States, 90723
United States, Missouri
Otsuka Investigative Site
St. Louis, Missouri, United States, 63118
United States, New Jersey
Otsuka Investigative Site
Willingboro, New Jersey, United States, 08046
United States, Texas
Otsuka Investigative Site
Austin, Texas, United States, 78756
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.

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Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT01870999     History of Changes
Other Study ID Numbers: 31-05-244
First Posted: June 6, 2013    Key Record Dates
Results First Posted: January 22, 2014
Last Update Posted: January 22, 2014
Last Verified: December 2013
Additional relevant MeSH terms:
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Aripiprazole
Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
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