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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Schizophrenia, Bipolar I Disorder

Intervention / Treatment
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* Drug: Aripiprazole
* Drug: Aripiprazole


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aripiprazole 2M LAI 960 mg: Schizophrenia or Bipolar I Disorder<br>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. | Drug: Aripiprazole<br>* Administered as an intramuscular (IM) depot injection.<br>* Other names: Lu AF41155;|
| Experimental: Aripiprazole IM Depot 400 mg: Schizophrenia or Bipolar I Disorder<br>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. | Drug: Aripiprazole<br>* Administered as an IM depot injection.<br>* Other names: Lu AF41155;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs) | 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. | 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) | 
| Number of Participants With Potentially Clinically Relevant Vital Signs Abnormalities | 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. | From first dose of study drug up to Day 225 | 
| Number of Participants With Potentially Clinically Relevant Electrocardiogram (ECG) Abnormalities | 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). | From first dose of study drug up to Day 225 | 
| Number of Participants With Potentially Clinically Relevant Clinical Laboratory Abnormalities | 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. | From first dose of study drug up to Day 225 | 
| Mean Change From Baseline in Simpson-Angus Neurologic Rating Scale (SAS) Total Score | 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. | Baseline, Week 32 | 
| Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Movement Score | 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. | Baseline, Week 32 | 
| Mean Change From Baseline in Barnes Akathisia Rating Score (BARS) Global Score | 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. | Baseline, Week 32 | 
| Visual Analog Scale (VAS) Scores for Pain Perception of Aripiprazole 2M LAI 960 mg | 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). | Day 1 (First injection) to Day 169 (Last injection) | 
| VAS Scores for Pain Perception of Aripiprazole IM Depot 400 mg | 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). | Day 1 (First injection) to Day 197 (Last injection) | 
| Number of Participants With Injection Site Evaluations (Pain, Redness, Swelling, Induration) Measured by Investigator Rating After Aripiprazole 2M LAI 960 mg 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. | Day 1 (First injection) to Day 169 (Last injection) | 
| Number of Participants With Injection Site Evaluations (Pain, Redness, Swelling, Induration) Measured by Investigator Rating After Aripiprazole IM Depot 400 mg 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. | Day 1 (First injection) to Day 197 (Last injection) | 
| Number of Participants With Suicidality as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) | 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. | Baseline to Day 225 | 
| Plasma Concentration of Aripiprazole 56 Days Postdose (C56) of Aripiprazole 2M LAI 960 mg After the Fourth Dose |  | Day 225 | 
| Plasma Concentration of Aripiprazole 28 Days Postdose (C28) of Aripiprazole IM Depot 400 mg After the Eighth Dose |  | 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 |  | 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 |  | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Aripiprazole After First and Fourth Doses of Aripiprazole 2M LAI 960 mg |  | 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 |  | 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 |  | 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 |  | Predose on Day 57 | 
| AUC0-28 After the Fourth Dose of Aripiprazole 2M LAI 960 mg |  | 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 |  | Days 204, 211, 218, and 225 | 
| Peak-to-Trough Percent Fluctuation (PTF%) After the Fourth Dose of Aripiprazole 2M LAI 960 mg | 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. | 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 | 
| Cmax of Aripiprazole After the First, Seventh, and Eighth Doses of Aripiprazole IM Depot 400 mg |  | 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 |  | 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 |  | 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 |  | Predose on Day 29 | 
| PTF% After the Eighth Dose of Aripiprazole IM Depot 400 mg | 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. | 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 | 
| Plasma Concentration of Aripiprazole 7 Days Post First Dose (C7) of Aripiprazole 2M LAI 960 mg |  | Day 8 | 
| Plasma Concentration of Aripiprazole Post First Dose (C14) of Aripiprazole IM Depot 400 mg |  | Day 15 | 
| Mean Change From Baseline in Positive and Negative Syndrome Scale Rating Criteria (PANSS) Total Score | 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. | Baseline, Week 32 | 
| Mean Change From Baseline in Clinical Global Impression - Severity Scale (CGI-S) Score | 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. | Baseline, Week 32 | 
| Mean Change From Baseline in Clinical Global Impression - Improvement Scale (CGI-I) Score | 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. | Baseline, Week 32 | 
| Mean Change From Baseline in Subjective Well-Being Under Neuroleptic Treatment-Short Form (SWN-S) Total Score | 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 | Baseline, Week 32 | 
| Mean Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | 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. | Baseline, Week 32 | 
| Mean Change From Baseline in Young Mania Rating Scale (YMRS) Total Score | 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. | Baseline, Week 32 | 
| Mean Change From Baseline in Clinical Global Impression - Bipolar Version (CGI-BP) Severity of Illness Score | 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. | Baseline, Week 32 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aripiprazole, Aripiprazole Intramuscular Depot, Gluteal Muscle, Long Acting Injection