Safety and Tolerability Study of Aripiprazole IM Depot in Adult Subjects With Schizophrenia

• ClinicalTrials.gov Identifier: NCT01909466
• Recruitment Status: Completed
• First Posted: July 26, 2013
• Results First Posted: June 2, 2015
• Last Update Posted: July 1, 2015
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborator: H. Lundbeck A/S
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Description

Brief Summary:

To determine the safety and tolerability of multiple-dose administrations of aripiprazole intramuscular (IM) depot in the deltoid muscle in adult subjects with schizophrenia

Condition or disease	Intervention/treatment	Phase
Schizophrenia; Mental Disorder; Nervous System Diseases	Drug: Aripiprazole, OPC-14597	Phase 1

Detailed Description:

This is a trial designed to assess the safety and tolerability of multiple-dose administrations of aripiprazole intramuscular (IM) depot in the deltoid muscle in adult subjects with schizophrenia. The trial consists of a 113 day treatment period with a 28 day followup. The trial population will include male and female subjects between 18 and 64 years (inclusive), with a current diagnosis of schizophrenia as defined by DSM-IV-TR criteria and a prior history of tolerating aripiprazole per investigator's judgement.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 141 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multiple Dose, Safety and Tolerability Study of Aripiprazole IM Depot Administered in the Deltoid Muscle in Adult Subjects With Schizophrenia
• Study Start Date: July 2013
• Actual Primary Completion Date: March 2014
• Actual Study Completion Date: April 2014

Arms and Interventions

Arm	Intervention/treatment
Gluteal Injection	Drug: Aripiprazole, OPC-14597; 5 monthly applications of 400 mg of aripiprazole IM depot, where the first application is in the gluteal or deltoid muscle followed by 4 monthly administrations to the deltoid muscle
Deltoid Injection	Drug: Aripiprazole, OPC-14597; 5 monthly applications of 400 mg of aripiprazole IM depot, where the first application is in the gluteal or deltoid muscle followed by 4 monthly administrations to the deltoid muscle

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events (AEs). [ Time Frame: AEs were recorded from the time the informed consent was signed until follow-up for 28 days after last ]
   AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug related by the investigator. A serious adverse event (SAE) was any untoward medical occurrence that resulted in death or was life threatening or required inpatient hospitalization or prolonged hospitalization. A treatment-emergent AE (TEAE) was defined as an AE that started after start of study medication or an AE that continued from baseline and that worsened, was serious, was study medication related, or resulted in death, discontinuation, interruption, or reduction of study medication.
2. Mean Visual Analog Scale (VAS) Score for Rating of Pain at the Injection Site. [ Time Frame: Days 1 and 113 ]
   Participants assessed the pain associated with injection of aripiprazole IM using the VAS instrument. This was done approximately 30 minutes pre-dose and 1 hour (±15 min) Post-dose on Days 1, 29, 57, 85 and 113. For the first injection, the pre-dose assessment was of the current injection site. For the injections 2 through 5, the pre-dose assessment was of the prior injection site. Investigator's Assessment of Most Recent Injection Site including pain, swelling, redness, and induration were reported in 4-point categorical scale (1 = absent, 2 = mild, 3 = moderate and 4 = severe) by first injection site at each injection.
3. Mean Change From Baseline in Suicidal Ideation Intensity Total Score Via Columbia-suicide Severity Rating Scale (C-SSRS). [ Time Frame: Baseline to Last Visit (Day 141) ]
   Suicidality was monitored throughout the trial using C-SSRS. The C-SSRS addresses the need for standardized classification of suicide reports to assess suicide risk. This scale consisted of Baseline evaluation that assessed the lifetime experience of the participant with suicidal events and suicidal ideation and a post baseline evaluation that focuses on suicidality since the last trial visit. The C-SSRS since last visit form were completed on Day 1 pre-dose and prior to dosing on Days 29, 57, 85, 113, 141/ Early Termination(ET) and prior to pharmacokinetics(PK) sampling on Days 8, 15, 22, 120, 127 and 134. The suicidal ideation intensity total score was the sum of suicidal ideation severity rating scores for frequency, duration, controllability, deterrents, and reasons for ideation. For each item, each participant got an intensity score from 0(none) to 5(worst). Therefore,the suicidal ideation intensity total score range from 0 to 25, with a score of 0 given for no suicidal ideation.
4. Mean Change From Baseline Measured by Extrapyramidal Symptoms (EPS) by Simpson-Angus Scale (SAS). [ Time Frame: Baseline to Week 20 ]
   The SAS consisted of a list of 10 symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). The SAS Total Score was the sum of the scores for all 10 items. SAS total score can range from 10 to 50. Each item was rated on a 5-point scale, with a score of 1 =absence of symptoms and a score of 5 =severe condition.
5. Mean Change From Baseline Measured by EPS by Abnormal Involuntary Movement Scale (AIMS). [ Time Frame: Baseline to Week 20 ]
   The AIMS assessment consisted of 10 items describing symptoms of dyskinesia. Facial and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk movements (item 7) were observed unobtrusively while the participant was at rest (e.g., in the waiting room), and the study physician would make global judgments on the participant's dyskinesia's (items 8 through 10). These items are rated on a five-point scale of severity from 0-4. The scale is rated from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe). Overall AIMS scores range from 0 to 42.
6. Mean Change From Baseline Measured by EPS by Barnes Akathisia Rating Scale (BARS). [ Time Frame: Baseline to Week 20 ]
   The BARS consisted of 4 items related to akathisia: objective observation of akathisia by the study physician, subjective feelings of restlessness by the participant, participant distress due to akathisia, and global evaluation of akathisia. To complete this scale, participants were observed while they were seated and then stood for a minimum of 2 minutes in each position. Symptoms observed in other situations (e.g., while engaged in neutral conversation or engaged in activity on the ward) may also be rated. Subjective phenomena were to be elicited by direct questioning. The first 3 items were rated on a 4-point scale, with a score of 0 = absence of symptoms and a score of 3 = severe condition. The global clinical evaluation were made on a 6-point scale, (0=absent, 1=questionable, 2=mild, 3=moderate, 4=marked, 5=severe).

Secondary Outcome Measures :

1. Mean Change From Baseline in Total Score of Positive and Negative Syndrome Scale (PANSS). [ Time Frame: Baseline to Week 20 ]
   The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
2. Mean Change From Baseline in PANSS Positive Sub-scale Score. [ Time Frame: Baseline to Week 20 ]
   The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS Positive Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
3. Mean Change From Baseline in PANSS Negative Sub-scale Score. [ Time Frame: Baseline to Week 20 ]
   The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
4. Mean Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score. [ Time Frame: Baseline to Week 20 ]
   The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the study physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the participant 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 participants.
5. Clinical Global Impression-Improvement (CGI-I) Score. [ Time Frame: Baseline to Week 20 ]
   The efficacy of trial medication were rated for each participant using the CGI-I scale. The study physician must rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared to the participant's condition a baseline. Response choices include: 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.
6. Mean Change From Baseline in Total Score of Subject Well-being Under Neuroleptic Treatment-Short Form (SWN-S). [ Time Frame: Baseline to Week 20+ ]
   The participant's feeling of their own well-being was assessed using the 20 question SWN-S. The SWN-S was a validated self-report instrument that evaluated the participant's perception of 1 being while receiving antipsychotic medication. The questionnaire consisted of 20 items and 5 subscales (mental functioning, social integration, emotional regulation, physical functioning, self-control) whose items followed in random order. For items marked with a '+', response choices and scoring were as follows: not at all = 1, hardly at all = 2, a little = 3, somewhat = 4, much = 5, very much = 6. For items marked with a '-', the scoring was reversed; response choices and scoring were as follows: not at all = 6, hardly at all = 5, a little = 4, somewhat = 3, much = 2, very much = 1. The total score from the scale ranges from 20 (bad subjective experience) to 120 (perfect subjective experience).
7. Mean Change From Baseline in Mental Functioning Score of SWN-S. [ Time Frame: Baseline to Week 20 ]
   The participant's feeling of their own well-being was assessed using the 20 question SWN-S. The SWN-S was a validated self-report instrument that evaluated the participant's perception of 1 being while receiving antipsychotic medication. The questionnaire consisted of 20 items and 5 subscales (mental functioning, social integration, emotional regulation, physical functioning, self-control) whose items followed in random order. For items marked with a '+', response choices and scoring were as follows: not at all = 1, hardly at all = 2, a little = 3, somewhat = 4, much = 5, very much = 6. For items marked with a '-', the scoring was reversed; response choices and scoring were as follows: not at all = 6, hardly at all = 5, a little = 4, somewhat = 3, much = 2, very much = 1. SWN-S subscale score's each item was rated on a score of 0 (none) to 6 (severe), with higher scores indicating stronger subjective feelings of deficit.
8. Mean Change From Baseline in Self Control Score of SWN-S. [ Time Frame: Baseline to Week 20 ]
   The participant's feeling of their own well-being was assessed using the 20 question SWN-S. The SWN-S was a validated self-report instrument that evaluated the participant's perception of 1 being while receiving antipsychotic medication. The questionnaire consisted of 20 items and 5 subscales (mental functioning, social integration, emotional regulation, physical functioning, self-control) whose items followed in random order. For items marked with a '+', response choices and scoring were as follows: not at all = 1, hardly at all = 2, a little = 3, somewhat = 4, much = 5, very much = 6. For items marked with a '-', the scoring was reversed; response choices and scoring were as follows: not at all = 6, hardly at all = 5, a little = 4, somewhat = 3, much = 2, very much = 1. SWN-S subscale score's each item was rated on a score of 0 (none) to 6 (severe), with higher scores indicating stronger subjective feelings of deficit.
9. Mean Change From Baseline in Physical Functioning Score of SWN-S. [ Time Frame: Baseline to Week 20 ]
   The participant's feeling of their own well-being was assessed using the 20 question SWN-S. The SWN-S was a validated self-report instrument that evaluated the participant's perception of 1 being while receiving antipsychotic medication. The questionnaire consisted of 20 items and 5 subscales (mental functioning, social integration, emotional regulation, physical functioning, self-control) whose items followed in random order. For items marked with a '+', response choices and scoring were as follows: not at all = 1, hardly at all = 2, a little = 3, somewhat = 4, much = 5, very much = 6. For items marked with a '-', the scoring was reversed; response choices and scoring were as follows: not at all = 6, hardly at all = 5, a little = 4, somewhat = 3, much = 2, very much = 1. SWN-S subscale score's each item was rated on a score of 0 (none) to 6 (severe), with higher scores indicating stronger subjective feelings of deficit.
10. Mean Change From Baseline in Emotional Regulation Score of SWN-S. [ Time Frame: Baseline to Week 20 ]
    The participant's feeling of their own well-being was assessed using the 20 question SWN-S. The SWN-S was a validated self-report instrument that evaluated the participant's perception of 1 being while receiving antipsychotic medication. The questionnaire consisted of 20 items and 5 subscales (mental functioning, social integration, emotional regulation, physical functioning, self-control) whose items followed in random order. For items marked with a '+', response choices and scoring were as follows: not at all = 1, hardly at all = 2, a little = 3, somewhat = 4, much = 5, very much = 6. For items marked with a '-', the scoring was reversed; response choices and scoring were as follows: not at all = 6, hardly at all = 5, a little = 4, somewhat = 3, much = 2, very much = 1. SWN-S subscale score's each item was rated on a score of 0 (none) to 6 (severe), with higher scores indicating stronger subjective feelings of deficit.
11. Mean Change From Baseline in Social Integration Score of SWN-S. [ Time Frame: Baseline to Week 20 ]
    The participant's feeling of their own well-being was assessed using the 20 question SWN-S. The SWN-S was a validated self-report instrument that evaluated the participant's perception of 1 being while receiving antipsychotic medication. The questionnaire consisted of 20 items and 5 subscales (mental functioning, social integration, emotional regulation, physical functioning, self-control) whose items followed in random order. For items marked with a '+', response choices and scoring were as follows: not at all = 1, hardly at all = 2, a little = 3, somewhat = 4, much = 5, very much = 6. For items marked with a '-', the scoring was reversed; response choices and scoring were as follows: not at all = 6, hardly at all = 5, a little = 4, somewhat = 3, much = 2, very much = 1. SWN-S subscale score's each item was rated on a score of 0 (none) to 6 (severe), with higher scores indicating stronger subjective feelings of deficit.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Male and female individuals between 18 and 64 years, inclusive, at the time of informed consent.
• Prior history of tolerating aripiprazole per investigator's judgement.

Exclusion Criteria:

• Subjects who have met DSMV-IV-TR criteria for substance dependence within the past 180 days.
• Subjects who use more than one antipsychotic medication at screening.
• Use of any CYP2D6 and CYP3A4 inhibitors, or CYP3A4 inducers within 14 days prior to dosing and for the duration of the trial.
• Subjects who participated in any clinical trial involving a psychotropic medication within 1 month prior to enrollment.
• Subjects currently in an acute relapse of schizophrenia.
• Subjects with a current DSMV-IV-TR diagnosis other than schizophrenia.
• Subjects who are considered treatment-resistant to antipsychotic medications.

Contacts and Locations

Locations

United States, California

Comprehensive Clinical Development

Cerritos, California, United States, 90703

Collaborative Neuroscience Network, Inc.

Garden Grove, California, United States, 92845

CNRI-San Diego

San Diego, California, United States, 92101

United States, District of Columbia

Comprehensive Clinical Development

Washington, District of Columbia, United States, 20016

United States, Florida

Scientific Clinical Research, Inc.

Ft. Lauderdale, Florida, United States, 33308

Compass Research North, LLC

Leesburg, Florida, United States, 34748

United States, Georgia

Atlanta Center for Medical Research

Atlanta, Georgia, United States, 30308

United States, Missouri

St. Louis Clinical Trials

St. Louis, Missouri, United States, 63118

United States, New Jersey

CRI Lifetree

Marlton, New Jersey, United States, 08053

United States, Pennsylvania

CRI Lifetree

Philadelphia, Pennsylvania, United States, 19139

United States, Texas

Community Clinical Research, Inc.

Austin, Texas, United States, 78754

Sponsors and Collaborators

Otsuka Pharmaceutical Development & Commercialization, Inc.

H. Lundbeck A/S

Investigators

• Study Director: Kimberly Largay, MD; Otsuka Pharmaceutical Development & Commercialization, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Raoufinia A, Peters-Strickland T, Nylander AG, Baker RA, Eramo A, Jin N, Bricmont P, Repella J, McQuade RD, Hertel P, Larsen F. Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration. Int J Neuropsychopharmacol. 2017 Apr 1;20(4):295-304. doi: 10.1093/ijnp/pyw116.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01909466
• Other Study ID Numbers: 31-12-298
• First Posted: July 26, 2013
• Results First Posted: June 2, 2015
• Last Update Posted: July 1, 2015
• Last Verified: June 2015

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

OPC-14597; Aripiprazole; Schizophrenia

Additional relevant MeSH terms:

Nervous System Diseases; Schizophrenia; Mental Disorders; Schizophrenia Spectrum and Other Psychotic 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