A Trial of Multiple-doses of Aripiprazole in Adults With Schizophrenia or Bipolar 1 Disorder

• ClinicalTrials.gov Identifier: NCT04030143
• Recruitment Status: Completed
• First Posted: July 23, 2019
• Results First Posted: November 18, 2023
• Last Update Posted: November 18, 2023
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

Tracking Information

• First Submitted Date: July 19, 2019
• First Posted Date: July 23, 2019
• Results First Submitted Date: September 22, 2023
• Results First Posted Date: November 18, 2023
• Last Update Posted Date: November 18, 2023
• Actual Study Start Date: August 1, 2019
• Actual Primary Completion Date: July 8, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 22, 2023)

• Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From first dose of study drug up to 56 days (2M LAI 960 mg) or 28 days (IM depot 400 mg) post last dose of study drug (up to approximately 11 months) ]
  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. A TEAE is defined as an AE that started after investigational medicinal product (IMP) treatment; or if the event was continuous from baseline and was serious, IMP-related, or resulted in death, discontinuation, interruption, or reduction of the IMP.
• Number of Participants With Potentially Clinically Relevant Vital Signs Abnormalities [ Time Frame: From first dose of study drug up to Day 225 ]
  Potentially clinically significant vital sign abnormalities included: heart rate supine (high: >120 beats per minute [BPM] and increase >=15 BPM; low: <50 BPM and decrease >=15 BPM), systolic blood pressure supine (high >180 (millimetres of mercury [mmHg] and increase >=20 mmHg); low: <90 mmHg and decrease >=20 mmHg), diastolic blood pressure supine (high: >105 mmHg and increase >=15 mmHg; low: <50 mmHg and decrease >=15 mmHg), heart rate standing (high: >120 BPM and increase >=15 BPM), systolic blood pressure standing (high: >180 mmHg and increase >= 20 mmHg; low: <90 mmHg and decrease >=20 mmHg), diastolic blood pressure standing (high: >105 mmHg and increase >=15 mmHg), weight in kilograms (kg) (high: increase >=7%; low: decrease >=7%), temperature (high: >=37.8 degree celsius [°C] and increase >=1.1°C), orthostatic hypotension (low: >=20 mmHg decrease in systolic blood pressure and >=25 BPM increase in heart rate from supine to standing.
• Number of Participants With Potentially Clinically Relevant Electrocardiogram (ECG) Abnormalities [ Time Frame: From first dose of study drug up to Day 225 ]
  Potentially clinically significant ECG abnormalities included rate: bradycardia (vent <=50 BPM] and decrease >=15 BPM); rhythm: sinus bradycardia (<= 50 BPM and decrease >= 15 BPM and no current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality); supraventricular premature beat (not present at baseline and present post baseline); ventricular premature beat (not present at baseline and present post baseline); conduction: right bundle branch block (not present at baseline and present post baseline); ST/T morphology: myocardial ischemia and symmetrical T-wave inversion (not present at baseline and present post baseline), QTcB, QTcF, and QTcN (>=450 milliseconds [msec] and >= 10% increase).
• Number of Participants With Potentially Clinically Relevant Clinical Laboratory Abnormalities [ Time Frame: From first dose of study drug up to Day 225 ]
  Potentially clinically relevant laboratory abnormalities included: In units per liter [U/L] (alanine aminotransferase: male[M]/female[F] >=3 x upper limit of normal (ULN); aspartate aminotransferase: M/F >= 3 x ULN; creatine kinase: M/F >= 3 x ULN); in milligrams per deciliter (mg/dL) (creatinine: M/F >= 2.0; glucose: M/F >= 200; urate: M >=10.5, F >=8.5); potassium [milliequivalents per liter (mEq/L)]: M/F >=5.5, in percentage (%) (eosinophils/leukocytes: M/F>=10%, hematocrit: M<=37%/F<=32% and 3 point decrease from baseline); hemoglobin (grams per deciliter [g/dL]): M<=11.5/F<=9.5; leukocytes [10^9 per liter (/L)]: M/F<=2.8 x 10^3 per microliters (/uL); platelets (10^9/L): M/F>=700 x 10^3/uL; glucose, urine and protein, urine: increase of >=2 units; and prolactin (nanograms per milliliter [ng/mL]: M/F > 1 x ULN.
• Mean Change From Baseline in Simpson-Angus Neurologic Rating Scale (SAS) Total Score [ Time Frame: Baseline, Week 32 ]
  The SAS scale is used to evaluate extrapyramidal symptoms (EPS) and consists 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). Each item is rated on a 5-point scale, with a score of range of 0 (absence of symptoms) to 4 (severe condition). The SAS total score is the sum of the scores for all 10 items, possible total score is 0 to 40. Negative change from baseline indicates less symptoms.
• Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Movement Score [ Time Frame: Baseline, Week 32 ]
  The AIMS assessment consists 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), dyskinesias (items 8 through 10). Each item is rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, aware/severe distress). AIMS movement score is the sum of the ratings for the first seven items with the possible total scores of 0 to 28. Negative change from baseline indicates less symptoms.
• Mean Change From Baseline in Barnes Akathisia Rating Score (BARS) Global Score [ Time Frame: Baseline, Week 32 ]
  The BARS consists of 4 items related to akathisia: objective observation of akathisia by the investigator, subjective feelings of restlessness by the participant, participant distress due to akathisia, and global evaluation of akathisia. The first 3 items are rated on a 4-point scale, with a score of 0 representing absence of symptoms and a score of 3 representing a severe condition. The global clinical evaluation is made on a 6-point scale, with 0 representing absence of symptoms and a score of 5 representing severe akathisia. Total BARS score ranges from 0 to 14 where lower scores indicate less symptoms and negative change from baseline indicate less symptoms.
• Visual Analog Scale (VAS) Scores for Pain Perception of Aripiprazole 2M LAI 960 mg [ Time Frame: Day 1 (First injection) to Day 169 (Last injection) ]
  Injection-site pain was evaluated by mean VAS scores as reported by the participant after each injection at visits where an injection occurred. The last injection was the final injection for any given participant. Ratings ranged from 0 (no pain) to 100 (unbearably painful).
• VAS Scores for Pain Perception of Aripiprazole IM Depot 400 mg [ Time Frame: Day 1 (First injection) to Day 197 (Last injection) ]
  Injection-site pain was evaluated by mean VAS scores as reported by the participant after each injection at visits where an injection occurred. The last injection was the final injection for any given participant. Ratings ranged from 0 (no pain) to 100 (unbearably painful).
• Number of Participants With Injection Site Evaluations (Pain, Redness, Swelling, Induration) Measured by Investigator Rating After Aripiprazole 2M LAI 960 mg Injection [ Time Frame: Day 1 (First injection) to Day 169 (Last injection) ]
  Injection-site reactions were assessed by the investigator (or qualified designee) and the participant. Investigators rated localized pain, redness, swelling, and induration at the most recent injection site using a 4-point categorical scale (absent, mild, moderate, severe). The participant indicated the degree of pain at the most recent injection site using a VAS instrument. Ratings included were: 0 = absent, 1 = mild, 2 = moderate, 3 = severe. The last injection was the final injection for any given participant.
• Number of Participants With Injection Site Evaluations (Pain, Redness, Swelling, Induration) Measured by Investigator Rating After Aripiprazole IM Depot 400 mg Injection [ Time Frame: Day 1 (First injection) to Day 197 (Last injection) ]
  Injection-site reactions were assessed by the investigator (or qualified designee) and the participant. Investigators rated localized pain, redness, swelling, and induration at the most recent injection site using a 4-point categorical scale (absent, mild, moderate, severe). The participant indicated the degree of pain at the most recent injection site using a VAS instrument. Ratings included were: 0 = absent, 1 = mild, 2 = moderate, 3 = severe. The last injection was the final injection for any given participant.
• Number of Participants With Suicidality as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline to Day 225 ]
  C-SSRS was used to assess the suicidality of participants during the study. The assessment included "yes" or "no" responses for 5 questions, each related to suicidal ideation (wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods, active suicidal ideation with some intent, active suicidal ideation with specific plan) and suicidal behavior (preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, suicide). Numeric ratings were provided for suicidal ideation: Score range of 1 (wish to be dead) to 5 (active suicidal ideation with specific plan and intent), higher total scores indicate more suicidal ideation; Suicidal behavior: Score range of 0 (no suicidal behavior) to 4 (actual suicide attempt), higher total scores indicate more suicidal behavior. Suicidality was defined as reporting any suicidal ideation or behavior.
• Plasma Concentration of Aripiprazole 56 Days Postdose (C56) of Aripiprazole 2M LAI 960 mg After the Fourth Dose [ Time Frame: Day 225 ]
• Plasma Concentration of Aripiprazole 28 Days Postdose (C28) of Aripiprazole IM Depot 400 mg After the Eighth Dose [ Time Frame: Day 225 ]
• Area Under the Plasma Concentration-Time Curve From Time 0 to 28 Days (AUC0-28) of Aripiprazole After the Seventh and Eighth Doses of Aripiprazole IM Depot 400 mg [ Time Frame: Days 169 (predose and 4, 8, 12 hours post dose), 170, 171, 173, 176, 178, 181, 183, 186, 190, 197 (predose and 4, 8, 12 hours post dose), 198, 199, 201, 204, 206, 209, 211, 214, 218, 225 ]
• Area Under the Plasma Concentration-Time Curve From Time 0 to 56 Days (AUC0-56) of Aripiprazole After the Fourth Dose of Aripiprazole 2M LAI 960 mg [ Time Frame: Days 169 (predose and 4, 8, 12 hours post dose), 170, 171, 173, 176, 178, 181, 183, 186, 190, 197, 204, 211, 218, and 225 ]

Original Primary Outcome Measures (submitted: July 19, 2019)

• Number of Participants Reporting One of More Treatment-Emergent Adverse Event (TEAE) [ Time Frame: Baseline to Day 225 ]
  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical trial where the participant is administered a medical product; it does not necessarily have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
• Number of Participants With a Markedly Abnormal Vital Signs Measurement [ Time Frame: Baseline to Day 225 ]
  Vital signs will include systolic and diastolic blood pressure, heart rate, and body temperature.
• Number of Participants With a Markedly Abnormal Electrocardiogram (ECG) Result [ Time Frame: Baseline to Day 225 ]
  The number of participants with any markedly abnormal electrocardiogram (ECG) collected throughout study
• Number of Participants With a Markedly Abnormal Clinical Laboratory Assessments [ Time Frame: Baseline to Day 225 ]
  The number of participants with any markedly abnormal standard safety laboratory values collected throughout study.
• Number of Participants With a Markedly Abnormal Physical Examinations [ Time Frame: Baseline to Day 225 ]
  The number of participants with any markedly abnormal physical examination results collected throughout study
• Mean Change From Baseline in Simpson-Angus Scale Neurologic Rating Scale (SAS) [ Time Frame: Baseline to Day 225 ]
  To assess the extrapyramidal symptoms. The SAS consists 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). Each item will be rated on a 5-point scale, with a score of 1 representing absence of symptoms and a score of 5 representing a severe condition. The cumulative score will range from 10 to 50.
• Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) [ Time Frame: Baseline to Day 225 ]
  To assess the extrapyramidal symptoms. The AIMS assessment consists 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) will be observed unobtrusively while the participant is at rest (eg, in the waiting room), and the investigators will also make global judgments on the participants dyskinesias (items 8 through 10). Each item will be rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, aware/severe distress). The cumulative score will range from 0 to 40.
• Mean Change From Baseline in Barnes Akathisia Rating Score (BARS) [ Time Frame: Baseline and Day 225 ]
  To assess the extrapyramidal symptoms. The BARS consists of 4 items related to akathisia: objective observation of akathisia by the investigator, subjective feelings of restlessness by the participant, participant distress due to akathisia, and global evaluation of akathisia. The first 3 items will be rated on a 4-point scale, with a score of 0 representing absence of symptoms and a score of 3 representing a severe condition. The global clinical evaluation will be made on a 6-point scale, with 0 representing absence of symptoms and a score of 5 representing severe akathisia.
• Mean Change From Baseline in Visual Analog Scale (VAS) Pain Perception Scores After The Last Dose [ Time Frame: 2M LAI: Baseline to Day 169; 1M depot injection: Baseline to Day 197 ]
  Participants will assess the perceived pain at the injection site associated with the injection of IMP using a visual analog scale (VAS). Participants randomized to 2M LAI will receive the last dose on Day 169, while participants randomized to 1M depot injection will receive the last dose on Day 197.
• Mean Change From Baseline in Investigators Assessment of The Injection Site Score After The Last Dose [ Time Frame: 2M LAI: Baseline to Day 169; 1M depot injection: Baseline to Day 197 ]
  The investigators or designees will assess the injection site. Participants randomized to 2M LAI will receive the last dose on Day 169, while participants randomized to 1M depot injection will receive the last dose on Day 197.
• Mean Change From Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline to Day 225 ]
  Suicidality will be monitored during the trial using the C-SSRS. The scale consists of a baseline evaluation that assesses the lifetime experience of the participant with suicide events and suicidal ideation and a post baseline evaluation that focuses on suicidality since the last assessment.
• Plasma Concentration of Aripiprazole on Day 225 [ Time Frame: Day 225 ]
• Area Under the Plasma Concentration-Time Curve From Time 0 to 28 Days (AUC0-28) Post 7th and 8th Dose of Aripiprazole (1M depot injection) [ Time Frame: 0-12 hours post dose on Days 169 and 197, and on Days 170, 171, 173, 176, 178, 181, 183, 186, 190, 198, 199, 201, 204, 206, 209, 211, 214, 218 and 225 ]
  Participants randomized to 1M depot injection will receive the 7th and 8th dose on Days 169 and 197 respectively.
• Area Under the Plasma Concentration-Time Curve From Time 0 to 56 Days (AUC0-56) Post Last Dose of Aripiprazole (2M LAI) [ Time Frame: 0-12 hours post dose on Day 169, and on Days 170, 171, 173, 176, 178, 181, 183, 186, 190, 197, 204, 211, 218 and Day 225 ]
  Participants randomized to 2M LAI will receive the last dose on Day 169.

Current Secondary Outcome Measures (submitted: October 27, 2023)

• Maximum Observed Plasma Concentration (Cmax) of Aripiprazole After First and Fourth Doses of Aripiprazole 2M LAI 960 mg [ Time Frame: Days 1(predose [within 2 hours(h) prior to dosing]&4,8,12 h postdose),2,3,5,8,10,13,15,18,22,29,36,43,50,57(predose),85,113(predose),141,169(predose [within 2 h prior to dosing]& 4,8,12 h postdose),170,171,173,176,178,181,183,186,190,197,204,211,218 & 225 ]
• Time to Reach the Maximum Plasma Concentration (Tmax) of Aripiprazole After First and Fourth Doses of Aripiprazole 2M LAI 960 mg [ Time Frame: Days 1(predose [within 2 hours(h) prior to dosing]&4,8,12 h postdose),2,3,5,8,10,13,15,18,22,29,36,43,50,57(predose),85,113(predose),141,169(predose [within 2 h prior to dosing]& 4,8,12 h postdose),170,171,173,176,178,181,183,186,190,197,204,211,218 & 225 ]
• AUC0-56 After the First Dose of Aripiprazole 2M LAI 960 mg [ Time Frame: Days 1 (predose and 4, 8, 12 hours post-dose), 2, 3, 5, 8, 10, 13, 15, 18, 22, 29, 36, 43, 50 and 57 (pre-dose) ]
• Plasma Concentration of Aripiprazole 56 Days (C56) After the First Dose of Aripiprazole 2M LAI 960 mg [ Time Frame: Predose on Day 57 ]
• AUC0-28 After the Fourth Dose of Aripiprazole 2M LAI 960 mg [ Time Frame: Days 169 (predose and 4, 8, 12 hours postdose), 170, 171, 173, 176, 178, 181, 183, 186, 190, and 197 ]
• Area Under the Plasma Concentration-Time Curve From Time 29 to 56 Days (AUC29-56) After the Fourth Dose of Aripiprazole 2M LAI 960 mg [ Time Frame: Days 204, 211, 218, and 225 ]
• Peak-to-Trough Percent Fluctuation (PTF%) After the Fourth Dose of Aripiprazole 2M LAI 960 mg [ Time Frame: Days 169 (Predose [within 2 hours prior to dosing] and 4, 8, 12 hours post dose), 170, 171, 173, 176, 178, 181, 183, 186, 190, 197, 204, 211, 218, and 225 ]
  PTF% was determined as 100*(Cmax - Cmin [minimum plasma concentration of the drug])/Caverage (average steady-state plasma drug concentration during multiple-dose administration) following fourth dose.
• Cmax of Aripiprazole After the First, Seventh, and Eighth Doses of Aripiprazole IM Depot 400 mg [ Time Frame: Predose [within 2 hours prior to dosing; 4,8,12h postdose] on Days 1,169,197; Predose on Days 29,57,85,113,141; and on Days 2, 3, 5, 8, 10, 13, 15, 18, 22, 170, 171, 173, 176, 178, 181, 183, 186, 190,198, 199, 201, 204, 206, 209, 211, 214, 218, 225 ]
• Tmax of Aripiprazole After the First, Seventh, and Eighth Doses of Aripiprazole IM Depot 400 mg [ Time Frame: Predose [within 2 hours prior to dosing; 4,8,12h postdose] on Days 1,169,197; Predose on Days 29,57,85,113,141; and on Days 2, 3, 5, 8, 10, 13, 15, 18, 22, 170, 171, 173, 176, 178, 181, 183, 186, 190,198, 199, 201, 204, 206, 209, 211, 214, 218, 225 ]
• AUC0-28 After the First Dose of Aripiprazole IM Depot 400 mg [ Time Frame: Days 1 (predose and 4, 8, and 12 hours postdose), 2, 3, 5, 8, 10, 13, 15, 18, 22 and 29 (predose) ]
• Plasma Concentration of Aripiprazole 28 Days (C28) After the First Dose of Aripiprazole IM Depot 400 mg [ Time Frame: Predose on Day 29 ]
• PTF% After the Eighth Dose of Aripiprazole IM Depot 400 mg [ Time Frame: Days 197 (Predose [within 2 hours prior to dosing] and 4, 8, 12 hours post dose),198, 199, 201, 204, 206, 209, 211, 214, 218, 225 ]
  PTF% was determined as 100*(Cmax - Cmin [minimum plasma concentration of the drug])/Caverage (average steady-state plasma drug concentration during multiple-dose administration) following eighth dose.
• Plasma Concentration of Aripiprazole 7 Days Post First Dose (C7) of Aripiprazole 2M LAI 960 mg [ Time Frame: Day 8 ]
• Plasma Concentration of Aripiprazole Post First Dose (C14) of Aripiprazole IM Depot 400 mg [ Time Frame: Day 15 ]
• Mean Change From Baseline in Positive and Negative Syndrome Scale Rating Criteria (PANSS) Total Score [ Time Frame: Baseline, Week 32 ]
  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). Higher scores indicate worse condition. The PANSS was assessed for schizophrenia participants only.
• Mean Change From Baseline in Clinical Global Impression - Severity Scale (CGI-S) Score [ Time Frame: Baseline, Week 32 ]
  The CGI-S is a standardized, clinician-administered global rating scale that measures disease severity. 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 participant at this time?" Response choices include: 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. The cumulative score range is 0-7. A higher score on the CGI-S represents a higher severity of disease. The CGI-S scale was assessed for schizophrenia participants only.
• Mean Change From Baseline in Clinical Global Impression - Improvement Scale (CGI-I) Score [ Time Frame: Baseline, Week 32 ]
  The CGI-I scale is a clinician rated scale which assesses the improvement of illness for each participant. To assess CGI-I, the rater or investigator rated the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared with the participant's condition at 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. Scores range from 0 to 7. Higher scores indicate worse condition.
• Mean Change From Baseline in Subjective Well-Being Under Neuroleptic Treatment-Short Form (SWN-S) Total Score [ Time Frame: Baseline, Week 32 ]
  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 well-being while receiving antipsychotic medication. The questionnaire consisted of 20 items (10 positive and 10 negative statements) and 5 subscales (mental functioning, social integration, emotional regulation, physical functioning, self-control) whose items followed in random order. For items marked with a '+', the response choices and scoring is not at all = 1, hardly at all = 2, a little = 3, somewhat = 4, much = 5, and very much = 6. For items marked with a '- ', the scoring is reversed; response choices and scoring are 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 1 (none) to 6 (severe), and total score ranged from 20 to 120, with higher scores indicating stronger subjective feeling
• Mean Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score [ Time Frame: Baseline, Week 32 ]
  The MADRS is a diagnostic questionnaire used by clinician to assess the participant's severity of depression. This scale consists of 10 items each with 7 defined grades of severity on 0 to 6 scale (reported sadness, apparent sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). MADRS total score is sum of 10 individual item scores ranging from 0-60 categorized as: 0 to 6: normal/symptoms absent, 7 to 19: mild depression, 20 to 34: moderate depression, and 35 to 60: severe depression. Higher score indicates more depressive symptoms. The MADRS was assessed for bipolar I disorder participants only.
• Mean Change From Baseline in Young Mania Rating Scale (YMRS) Total Score [ Time Frame: Baseline, Week 32 ]
  The YMRS is an 11-item, multiple-choice diagnostic questionnaire which psychiatrists use to assess the core symptoms of mania and is based on the participants subjective report of their condition. There are four items that are graded on a 0 to 8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale. Total score is summed of 11 items. Total score range is from 0 to 60 and the higher score represent a worse outcome. The YMRS was assessed for bipolar I disorder participants only.
• Mean Change From Baseline in Clinical Global Impression - Bipolar Version (CGI-BP) Severity of Illness Score [ Time Frame: Baseline, Week 32 ]
  The CGI-BP scale refers to the global impression of the participants with respect to bipolar disorder. The scale rates the participant's severity of illness (CGI-BP-Severity: mania, depression, and overall bipolar illness) and change from preceding phase (CGI-BP change from preceding phase: mania, depression, and overall bipolar illness) based on a 7-point scale ranging from 1 (normal, not ill) to 7 (very severely ill). A negative change score signifies improvement. The CGI-BP was assessed for bipolar I disorder participants only.

Original Secondary Outcome Measures (submitted: July 19, 2019)

• Maximum Observed Plasma Concentration (Cmax) of Aripiprazole [ Time Frame: 2M LAI: 0-12 hours post dose on Day 1 and 169; 1M depot injection: 0-12 hours on Day 1, 169 and 197 ]
  Cmax will be measured after the 1st and 4th dose of aripiprazole 2M LAI and after the 1st, 7th and 8th dose of aripiprazole 1M depot injection.
• Time to Reach the Maximum Plasma Concentration (Tmax) of Aripiprazole [ Time Frame: 2M LAI: 0-12 hours post dose on Day 1 and 169; 1M depot injection: 0-12 hours on Day 1, 169 and 197 ]
  Tmax will be measured after the 1st and 4th dose of aripiprazole 2M LAI and after the 1st, 7th and 8th dose of aripiprazole 1M depot injection.
• Area Under the Plasma Concentration-Time Curve From Time 0 to 28 Days (AUC0-28) Post First Dose of Aripiprazole (1M depot injection) [ Time Frame: 0-12 hours post first dose on Day 1, and Days 2, 3, 5, 8, 10, 13, 15, 18, 22, and 29 ]
• Area Under the Plasma Concentration-Time Curve From Time 0 to 56 Days (AUC0-56) Post First Dose of Aripiprazole (2M LAI) [ Time Frame: 0-12 hours post first dose on Day 1, and Days 2, 3, 5, 8, 10, 13, 15, 18, 22, 29, 36, 43, 50 and 57 ]
• Plasma Concentration of Aripiprazole 28 Days (C28) Post First Dose (1M depot injection) [ Time Frame: Day 29 ]
• Plasma Concentration of Aripiprazole 56 Days (C56) Post First Dose (2M LAI) [ Time Frame: Day 57 ]
• Area Under the Plasma Concentration-Time Curve From Time 0 to 28 Days (AUC0-28) Post Last Dose for Aripiprazole (2M LAI only) [ Time Frame: 0-12 hours post last dose on Day 169, and on Days 170, 171, 173, 176, 178, 181, 183, 186, 190, and 197 ]
• Plasma Concentration of Aripiprazole 28 to 56 Days (C28) Post Last Dose (2M LAI only) [ Time Frame: Day 197 to 225 ]
  Participants receiving 2M LAI will receive the last dose on Day 169.
• Peak-to-Trough Percent Fluctuation (PTF%) After the Last Dose of Aripiprazole [ Time Frame: 2M LAI: 0-12 hours post dose on Day 169, and at multiple time points from Day 170 to Day 255; 1M depot injection: 0-12 hours post dose on Day 197 and at multiple timepoints from Day 198 to 225 ]
• Plasma Concentration of Aripiprazole 14 Days (C14) Post First Dose (1M depot injection) [ Time Frame: Day 15 ]
• Plasma Concentration of Aripiprazole 7 Days (C7) Post First Dose (2M LAI) [ Time Frame: Day 8 ]
• Change from Baseline in Positive and Negative Syndrome Scale Rating Criteria (PANSS) [ Time Frame: Baseline to Day 225 ]
  The PANSS consists of 3 subscales containing a total of 30 symptoms constructs developed to asses both the positive and negative symptom of participants with schizophrenia. For each symptom constructs, severity is 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 cumulative score ranges from 30 to 210.
• Change from Baseline in Clinical Global Impression - Severity Scale (CGI-S) [ Time Frame: Baseline to Day 225 ]
  The CGI-S is a 7-point scale used to measure the severity of illness for each participant. Response choices include: 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.
• Change from Baseline in Clinical Global Impression - Improvement Scale (CGI-I) [ Time Frame: Day 57 to Day 225 ]
  The CGI-I scale measures the improvement of illness for each participant. Response choices include: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no changed, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
• Change from Baseline in Subjective Well-Being Under Neuroleptic Treatment-Short Form (SWN-S) [ Time Frame: Baseline to Day 225 ]
  The SWN-S is a participant self-rated scale developed to evaluate the participants perception of well-being while receiving antipsychotic medication. The questionnaire consists of 20 items and 5 subscales (mental functioning, social integration, emotional regulation, physical functioning, and self control). For items marked with a '+', items are rated 1 = not at all to 6 = very much. For items marked with a '-' items are rated 1 = very much to 6 = hardly at all. Total possible scores range from 20-120.
• Change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) [ Time Frame: Baseline to Day 225 ]
  The MADRS measures symptoms of depression and is administered using a structured interview guide. The scale consists of 10 items, each with 7 defined grades of severity (0-6). Total scores ranges from 0-60 and a higher score indicates more depressive symptoms.
• Change from Baseline in Young Mania Rating Scale (YMRS) [ Time Frame: Baseline to Day 225 ]
  The YMRS is an 11-item, multiple-choice diagnostic questionnaire which psychiatrists use to assess the core symptoms of mania and is based on the participants subjective report of their condition. There are four items that are graded on a 0 to 8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale. Total score is summed of 11 items. Total score rage is from 0 to 60 and the higher score represent a worse outcome.
• Change from Baseline in Clinical Global Impression - Bipolar Version (CGI-BP) [ Time Frame: Baseline to Day 225 ]
  The CGI-BP scale refers to the global impression of the participants with respect to bipolar disorder. The scale rates the participant's severity of illness (CGI-BP-Severity: mania, depression, and overall bipolar illness) and change from preceding phase (CGI-BP change from preceding phase: mania, depression, and overall bipolar illness) based on a 7-point scale from 1 ('normal, not ill') to 7 ('very severely ill').

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Trial of Multiple-doses of Aripiprazole in Adults With Schizophrenia or Bipolar 1 Disorder
• Official Title: A Phase 1b, Open-label, Multiple-dose, Randomized, Parallel-arm, Safety, Tolerability, and Pharmacokinetic Trial of Aripiprazole Intramuscular Depot Administered in the Gluteal Muscle in Adult Subjects With Schizophrenia or Bipolar I Disorder
• Brief Summary: The purpose of this trial is to determine the safety and tolerability of multiple-dose administrations of aripiprazole, to establish the similarity of aripiprazole concentrations on the last day of the dosing interval following the final administration of aripiprazole into the gluteal muscle site, and to establish the similarity of aripiprazole exposure over the dosing interval following the administration of aripiprazole into the gluteal muscle site in adult participants with schizophrenia or bipolar I disorder.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Schizophrenia
• Bipolar I Disorder

Intervention

• Drug: Aripiprazole
  Administered as an intramuscular (IM) depot injection.
  Other Names:

  • OPC-14597
  • Lu AF41155
• Drug: Aripiprazole
  Administered as an IM depot injection.
  Other Names:

  • OPC-14597
  • Lu AF41155

Study Arms

• Experimental: Aripiprazole 2M LAI 960 mg: Schizophrenia or Bipolar I Disorder
  Participants with schizophrenia or bipolar I disorder received aripiprazole 2 month (2M) long-acting injection (LAI) 960 milligrams (mg) for a total of 4 injections administered every 56 days (± 2 days) over the course of 32 weeks.
  Intervention: Drug: Aripiprazole
• Experimental: Aripiprazole IM Depot 400 mg: Schizophrenia or Bipolar I Disorder
  Participants with schizophrenia or bipolar I disorder received aripiprazole IM 400 mg, for a total of 8 injections administered every 28 days (± 2 days) over the course of 32 weeks.
  Intervention: Drug: Aripiprazole

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 5, 2019): 266
• Original Estimated Enrollment (submitted: July 19, 2019): 258
• Actual Study Completion Date: July 8, 2020
• Actual Primary Completion Date: July 8, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• A current diagnosis of schizophrenia or bipolar I disorder, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.
• Body mass index of 18 to 35 kilograms per meter square (kg/m^2).
• On a stable dose of an atypical oral antipsychotic medication for at least 2 months prior to screening.

Exclusion Criteria:

• Participants who have:

  • Met DSM-5 criteria for substance use disorder within the past 180 days.
  • A positive drug screen for drugs of abuse
• Use of any psychotropic medications other than their current non-aripiprazole antipsychotic or mood stabilizer(s) medication; or participants who use more than one antipsychotic or mood stabilizer(s) medication at screening.
• Females who are pregnant, breast-feeding, lactating, and/or have a positive pregnancy test result prior to receiving investigational medicinal product (IMP). A negative serum pregnancy test must be confirmed prior to the first dose of IMP for all female participants.
• Any major surgery within 30 days prior to enrollment or scheduled/elective surgery during the trial.
• Evidence of organ dysfunction or any clinically significant deviation from normal in the physical, electrocardiographic, or clinical laboratory examinations.
• Participants currently in an acute relapse of schizophrenia.
• Participants with a current DSM-5 diagnosis other than schizophrenia or bipolar I disorder, including schizoaffective disorder, major depressive disorder, delirium, dementia, amnestic, or other cognitive disorders. Also, participants with borderline, paranoid, histrionic, or antisocial personality disorder.
• Participants with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia.
• History of any significant drug allergy or known or suspected hypersensitivity, in particular to aripiprazole or other quinolinones.
• History of or current hepatitis or acquired immunodeficiency syndrome or carriers of Hepatitis B surface antigen (HBsAg) or Hepatitis C antibodies (anti-HCV), and/or Human immunodeficiency virus (HIV) antibodies.
• Participants deemed intolerant of receiving injections.
• Participants who have had electroconvulsive therapy within 2 months of administration of IMP.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 64 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04030143
• Other Study ID Numbers: 031-201-00181
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• Access Criteria: Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to clinicaltransparency@Otsuka-us.com
• URL: https://clinical-trials.otsuka.com

• Current Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Verification Date: October 2023