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

Schizophrenia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04030143
• Other study ID #: 031-201-00181
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: August 1, 2019
• Est. completion date: July 8, 2020

Study information

• Verified date: October 2023
• Source: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 266
• Est. completion date: July 8, 2020
• Est. primary completion date: July 8, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

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.

Related Conditions & MeSH terms

• Bipolar I Disorder
• Schizophrenia

Intervention

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

Locations

Country	Name	City	State
United States	Atlanta Center for Medical Research - Atlanta	Atlanta	Georgia
United States	Community Clinical Research	Austin	Texas
United States	CITrials - Bellflower	Bellflower	California
United States	Carolina Clinical Trials	Charleston	South Carolina
United States	Midwest Clinical Research Center	Dayton	Ohio
United States	CBH Health	Gaithersburg	Maryland
United States	Collaborative Neuroscience Network	Garden Grove	California
United States	California Clinical Trials Medical Group	Glendale	California
United States	Research Centers of America	Hollywood	Florida
United States	Altea Research Institute - Las Vegas	Las Vegas	Nevada
United States	Synergy Research Centers	Lemon Grove	California
United States	Woodland International Research Group	Little Rock	Arkansas
United States	Hassman Research Institute	Marlton	New Jersey
United States	Segal Institute For Clinical Research - West Broward Outpatient Clinic	Miami Lakes	Florida
United States	NRC Research Institute	Orange	California
United States	Woodland International Research Group	Rogers	Arkansas
United States	St. Louis Clinical Trials	Saint Louis	Missouri
United States	California Neuropsychopharmacology Clinical Research Institute San Diego	San Diego	California
United States	Collaborative Neuroscience Network - South Bay	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Otsuka Pharmaceutical Development & Commercialization, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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
Primary	Plasma Concentration of Aripiprazole 56 Days Postdose (C56) of Aripiprazole 2M LAI 960 mg After the Fourth Dose		Day 225
Primary	Plasma Concentration of Aripiprazole 28 Days Postdose (C28) of Aripiprazole IM Depot 400 mg After the Eighth Dose		Day 225
Primary	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
Primary	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	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
Secondary	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
Secondary	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)
Secondary	Plasma Concentration of Aripiprazole 56 Days (C56) After the First Dose of Aripiprazole 2M LAI 960 mg		Predose on Day 57
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	Plasma Concentration of Aripiprazole 28 Days (C28) After the First Dose of Aripiprazole IM Depot 400 mg		Predose on Day 29
Secondary	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
Secondary	Plasma Concentration of Aripiprazole 7 Days Post First Dose (C7) of Aripiprazole 2M LAI 960 mg		Day 8
Secondary	Plasma Concentration of Aripiprazole Post First Dose (C14) of Aripiprazole IM Depot 400 mg		Day 15
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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