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

NCT04030143 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 031-201-00181
• Study Type: interventional
• Target: 266
• Locations: 1 country
• Sites: 19

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.

Conditions

Schizophrenia; Bipolar I Disorder

Keywords

Aripiprazole; Aripiprazole Intramuscular Depot; Gluteal Muscle; Long Acting Injection

Outcome Measures

Primary Outcomes (16)

• 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 Outcomes (21)

• 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

Study Arms (2)

Aripiprazole 2M LAI 960 mg: Schizophrenia or Bipolar I Disorder

EXPERIMENTAL

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

Aripiprazole IM Depot 400 mg: Schizophrenia or Bipolar I Disorder

EXPERIMENTAL

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

Interventions

Aripiprazole DRUG

Administered as an intramuscular (IM) depot injection.

Also known as: OPC-14597, Lu AF41155

Aripiprazole 2M LAI 960 mg: Schizophrenia or Bipolar I Disorder

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (19)

Woodland International Research Group

Little Rock, Arkansas, 72211, United States

Location

Woodland International Research Group

Rogers, Arkansas, 72758, United States

Location

CITrials - Bellflower

Bellflower, California, 90706, United States

Location

Collaborative Neuroscience Network

Garden Grove, California, 92845, United States

Location

California Clinical Trials Medical Group

Glendale, California, 91206, United States

Location

Synergy Research Centers

Lemon Grove, California, 91945, United States

Location

NRC Research Institute

Orange, California, 92868, United States

Location

California Neuropsychopharmacology Clinical Research Institute San Diego

San Diego, California, 92102, United States

Location

Collaborative Neuroscience Network - South Bay

Torrance, California, 90502, United States

Location

Research Centers of America

Hollywood, Florida, 33024, United States

Location

Segal Institute For Clinical Research - West Broward Outpatient Clinic

Miami Lakes, Florida, 33016, United States

Location

Atlanta Center for Medical Research - Atlanta

Atlanta, Georgia, 30331, United States

Location

CBH Health

Gaithersburg, Maryland, 20877, United States

Location

St. Louis Clinical Trials

St Louis, Missouri, 63141, United States

Location

Altea Research Institute - Las Vegas

Las Vegas, Nevada, 89102, United States

Location

Hassman Research Institute

Marlton, New Jersey, 08009, United States

Location

Midwest Clinical Research Center

Dayton, Ohio, 45417, United States

Location

Carolina Clinical Trials

Charleston, South Carolina, 29407, United States

Location

Community Clinical Research

Austin, Texas, 78754, United States

Location

Related Publications (3)

• Citrome L, Such P, Yildirim M, Madera-McDonough J, Beckham C, Zhang Z, Larsen F, Harlin M. Safety and Efficacy of Aripiprazole 2-Month Ready-to-Use 960 mg: Secondary Analysis of Outcomes in Adult Patients With Schizophrenia in a Randomized, Open-label, Parallel-Arm, Pivotal Study. J Clin Psychiatry. 2023 Sep 4;84(5):23m14873. doi: 10.4088/JCP.23m14873.

  PMID: 37672016 DERIVED

• McIntyre RS, Such P, Yildirim M, Madera-McDonough J, Zhang Z, Larsen F, Harlin M. Safety and efficacy of aripiprazole 2-month ready-to-use 960 mg: secondary analysis of outcomes in adult patients with bipolar I disorder in a randomized, open-label, parallel-arm, pivotal study. Curr Med Res Opin. 2023 Jul;39(7):1021-1030. doi: 10.1080/03007995.2023.2219155. Epub 2023 Jun 9.

  PMID: 37272079 DERIVED

• Harlin M, Yildirim M, Such P, Madera-McDonough J, Jan M, Jin N, Watkin S, Larsen F. A Randomized, Open-Label, Multiple-Dose, Parallel-Arm, Pivotal Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Aripiprazole 2-Month Long-Acting Injectable in Adults With Schizophrenia or Bipolar I Disorder. CNS Drugs. 2023 Apr;37(4):337-350. doi: 10.1007/s40263-023-00996-8. Epub 2023 Mar 24.

  PMID: 36961650 DERIVED

MeSH Terms

Conditions

Schizophrenia

Interventions

Aripiprazole

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Global Clinical Development
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.

clinicaltransparency@otsuka-us.com

1-609-524-6788

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2019
• First Posted: July 23, 2019
• Study Start: August 1, 2019
• Primary Completion: July 8, 2020
• Study Completion: July 8, 2020
• Last Updated: November 18, 2023
• Results First Posted: November 18, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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

Locations

US (19)