An Open Label Study of Aripiprazole Intramuscular Injection in Subjects With Schizophrenia

An Open-label, Randomized, Parallel Arm, Bioavailability Trial of Aripiprazole IM Depot Administered in the Deltoid or Gluteal Muscle in Adult Subjects With Schizophrenia

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01646827

Enrollment

Registered

2012-07-20

Start date

2012-05-31

Completion date

2013-04-30

Last updated

2014-07-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Schizophrenia

Keywords

Schizophrenia, extended release antipsychotic

Brief summary

The purpose of this study is to determine whether aripiprazole injection into the shoulder or the buttocks produces similar effects in the body

Detailed description

Extended-release gluteal intramuscular (IM) injection of aripiprazole has been tested in subjects with schizophrenia for safety and tolerability. This study will compare the gluteal IM aripiprazole injection with deltoid IM aripiprazole injection for safety and tolerability.

Interventions

DRUGAripiprazole IM Depot

One injection of 400 mg aripiprazole IM depot

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 64 Years

Healthy volunteers

Inclusion criteria

* Diagnosis of schizophrenia * Stabilized on oral antipsychotic medication * Good physical health * BMI 18 to 35 kg/m2 * Prior history of tolerating aripiprazole

Exclusion criteria

* Sexually active males who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during the trial and for 180 days following the last dose of trial medication, or have not had an orchidectomy or sexually active females of childbearing potential who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during the trial and for 150 days following the last dose of trial medication. Abstinence will be permitted if it is confirmed and documented at every trial visit. If employing birth control, 2 of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, birth control depot injections, implant, condom or sponge with spermicide. * Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the past 180 days; including alcohol and benzodiazepines, but excluding caffeine and nicotine. * Subjects with a positive drug screen for cocaine or other drugs of abuse (excluding stimulants and other prescribed medications and marijuana). * Use of any psychotropic medications other than their current antipsychotic medication. * Use of any CYP2D6 and CYP3A4 inhibitors, or CYP3A4 inducers within 14 days (fluoxetine 28 days) prior to dosing and for the duration of the trial. * Females who are pregnant or lactating. * Subjects who had participated in a previous IM depot trial within the last one year; or who had previously enrolled and received trial medication in an aripiprazole IM depot clinical trial. * Any major surgery within 30 days prior to enrollment. * Evidence of organ dysfunction or any clinically significant deviation from normal in physical, electrocardiographic, or clinical laboratory examinations. * Subjects who have a significant risk of committing suicide based on history, routine psychiatric status examination, investigator's judgment, or who have an answer of yes on questions 4 or 5 (current or over the last 30 days) on the Baseline/Screening version of the Columbia Suicide Severity Rating Scale (C-SSRS). * Subjects currently in an acute relapse of schizophrenia. * Subjects with a current DSM-IV-TR diagnosis other than schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar disorder, delirium, dementia, amnestic or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid or antisocial personality disorder. * Subjects who were considered treatment-resistant to antipsychotic medication. * Subjects who have had electroconvulsive therapy within 2 months of administration of trial drug. * Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia as assessed by the investigator. * Any other sound medical reason not to be entered into the trial, as determined by the clinical investigator. * Subjects who are known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones.

Design outcomes

Primary

Measure	Time frame	Description
Maximum Observed Plasma Concentration (Cmax) of Aripriprazole	Day 1: 4 hr, 8 hr, and 12 hr post dose, Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112 and 126/Early termination	Relative bioavailability (Frel) of aripiprazole intramuscular (IM) depot injected in the deltoid muscle compared to the gluteal muscle based on aripiprazole maximum (peak) plasma concentrations (Cmax) PK parameter.
Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Aripiprazole	Day 1: 4 hr, 8 hr, and 12 hr post dose, Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112 and 126/Early termination	Relative bioavailability (Frel) of aripiprazole IM depot injected in the deltoid muscle compared to the gluteal muscle based on area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUCt), AUC time curve 28, and AUC from time zero to infinity PK parameters.
Maximum Observed Plasma Concentration (Cmax) of Dehydro-Aripiprazole	Day 1: 4 hr, 8 hr, and 12 hr post dose, Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112 and 126/Early termination	Relative bioavailability (Frel) of aripiprazole intramuscular (IM) depot injected in the deltoid muscle compared to the gluteal muscle based on aripiprazole maximum (peak) plasma concentrations (Cmax) PK parameter.
Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Dehydro-Aripiprazole	Day 1: 4 hr, 8 hr, and 12 hr post dose, Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112 and 126/Early termination	Relative bioavailability (Frel) of aripiprazole IM depot injected in the deltoid muscle compared to the gluteal muscle based on area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUCt), AUC time curve 28 and AUC from time zero to infinity PK parameters.

Secondary

Measure	Time frame	Description
Number of Participants With Vital Signs of Potential Clinical Relevance-Heart Rate	Day 1, Day 14, Day 28 and Day 126/Early termination	Vital sign assessment included heart rate (supine and standing). Heart rate with increase or decrease of \>/= 15 beats per minute were recorded.
Number of Participants With Electrocardiogram (ECG) Measurements of Potential Clinical Relevance	Day 1, Day 14, Day 28 and Day 126/Early termination	Three 12 lead ECGs were performed approximately 5 minutes apart at each time point. The participant were supine and at rest (for at least 10 minutes) prior to the first ECG and will remain supine through the final ECG. Based on criteria for identifying ECG measurements of potential clinical relevance, the abnormal values were noted. Some of the criteria are as follows: For bradycardia: ≤ 50 beats per minute (bpm); and for increase in QTc: QTc ≥ 450msec.
Number of Participants Reporting Treatment Emergent Adverse Events (TEAE).	Starting at the time the ICF was signed to Day 126/Early termination	Safety was measured according to standard adverse event collection as described in the adverse event section of the results.
Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale.	Screening, Baseline, Week 1, Week 2, Week 8, Week 18 visit and Last visit.	This 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 trial visit.
Visual Analog Scale (VAS) Score at Day 1, Day 14, Day 28 and Last Visit.	Day 1, Day 14, Day 28 and last visit	Injection site pain was assessed using a VAS, which was completed by the trial participant, and the investigator's assessment of most recent injection site, which was completed by the investigator. VAS is 100 mm line, 0=no pain, 100=unbearably painful.
Number of Participants With Laboratory Values of Potential Clinical Relevance.	Day 1, Day 28, Day 126/Early termination	The laboratory tests were collected and processed in accordance with directions from the clinical chemistry laboratory. Based on criteria for identifying laboratory values of potential clinical relevance, the abnormal values were noted. Some of the criteria are as follows: For fasting triglycerides: men: ≥ 160 mg/dL and women: ≥ 120 mg/dL; Fasting glucose: ≥ 115 mg/dL; Prolactin: \> upper limit of normal (ULN); Neutrophils: ≤ 1,500/mm3; and Creatine phosphokinase: ≥ 3 x ULN.
Number of Participants With Vital Signs of Potential Clinical Relevance-Blood Pressure	Day 1, Day 14, Day 28 and Day 126/Early termination	Vital sign assessment included orthostatic (supine and standing) blood pressure. Orthostatic assessments were made after participants had been in the supine position for at least 5 minutes and again after participants had been standing for 2 minutes, but not more than 3 minutes. Orthostatic hypotension defined as \>/= 20 mm Hg decrease in systolic blood pressure and \>/= 25 beats per minute increase in heart rate from supine to standing.
Number of Participants With Vital Signs of Potential Clinical Relevance-Temperature	Day 1, Day 14, Day 28 and Day 126/Early termination	Vital sign assessment included body temperature measured in centigrade(C). Temperatures \>=37.8°C and increase of \>= 1.1°C were recorded.

Countries

United States

Participant flow

Recruitment details

This report presents results of a study on 37 adults with schizophrenia, conducted at 6 centers in the United States.

Pre-assignment details

Participants were randomized 1:1 to receive a single dose of aripiprazole intramuscular (IM) depot (400 mg) in either the deltoid muscle or gluteal muscle according to the randomization schedule.

Participants by arm

Arm	Count
Aripiprazole IM Depot 400 mg: Deltoid The participants in this group received single dose of aripiprazole IM depot (400 mg) injection in the deltoid muscle.	18
Aripiprazole IM Depot 400 mg: Gluteal The participants in this group received single dose of aripiprazole IM depot (400 mg) injection in the gluteal muscle.	19
Total	37

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	0	3
Overall Study	Physician Decision	1	2
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Aripiprazole IM Depot 400 mg: Deltoid	Aripiprazole IM Depot 400 mg: Gluteal	Total
Age, Continuous	43.1 Years STANDARD_DEVIATION 11	45.9 Years STANDARD_DEVIATION 7.3	44.5 Years STANDARD_DEVIATION 9.3
Sex: Female, Male Female	6 Participants	4 Participants	10 Participants
Sex: Female, Male Male	12 Participants	15 Participants	27 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	14 / 17	18 / 18
serious Total, serious adverse events	0 / 17	0 / 18

Outcome results

Primary

Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Aripiprazole

Relative bioavailability (Frel) of aripiprazole IM depot injected in the deltoid muscle compared to the gluteal muscle based on area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUCt), AUC time curve 28, and AUC from time zero to infinity PK parameters.

Time frame: Day 1: 4 hr, 8 hr, and 12 hr post dose, Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112 and 126/Early termination

Population: The dataset for the PK analysis consisted of all dosed subjects who had evaluable aripiprazole and dehydro-aripiprazole PK parameters.

Arm	Measure	Group	Value (MEAN)	Dispersion
Aripiprazole IM Depot 400 mg: Deltoid	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Aripiprazole	AUC infinity (n=16,14)	7590 ng day/mL	Standard Deviation 2590
Aripiprazole IM Depot 400 mg: Deltoid	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Aripiprazole	AUC 28 (n=16,17)	3120 ng day/mL	Standard Deviation 1150
Aripiprazole IM Depot 400 mg: Deltoid	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Aripiprazole	AUC t (n=16,17)	7360 ng day/mL	Standard Deviation 2420
Aripiprazole IM Depot 400 mg: Gluteal	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Aripiprazole	AUC infinity (n=16,14)	7920 ng day/mL	Standard Deviation 2580
Aripiprazole IM Depot 400 mg: Gluteal	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Aripiprazole	AUC 28 (n=16,17)	2380 ng day/mL	Standard Deviation 1410
Aripiprazole IM Depot 400 mg: Gluteal	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Aripiprazole	AUC t (n=16,17)	7340 ng day/mL	Standard Deviation 2360

Primary

Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Dehydro-Aripiprazole

Time frame: Day 1: 4 hr, 8 hr, and 12 hr post dose, Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112 and 126/Early termination

Population: The dataset for the PK analysis consisted of all dosed subjects who had evaluable aripiprazole and dehydro-aripiprazole PK parameters.

Arm	Measure	Group	Value (MEAN)	Dispersion
Aripiprazole IM Depot 400 mg: Deltoid	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Dehydro-Aripiprazole	AUC infinity (n=16,14)	2520 ng day/mL	Standard Deviation 836
Aripiprazole IM Depot 400 mg: Deltoid	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Dehydro-Aripiprazole	AUC 28 (n=16,17)	886 ng day/mL	Standard Deviation 445
Aripiprazole IM Depot 400 mg: Deltoid	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Dehydro-Aripiprazole	AUC t (n=16,17)	2420 ng day/mL	Standard Deviation 805
Aripiprazole IM Depot 400 mg: Gluteal	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Dehydro-Aripiprazole	AUC infinity (n=16,14)	2230 ng day/mL	Standard Deviation 630
Aripiprazole IM Depot 400 mg: Gluteal	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Dehydro-Aripiprazole	AUC 28 (n=16,17)	538 ng day/mL	Standard Deviation 305
Aripiprazole IM Depot 400 mg: Gluteal	Area Under the Concentration-Time Curve Infinity (AUC Infinity); Area Under the Concentration-Time Curve 28 (AUC 28), and Area Under the Concentration-Time Curve t (AUC t): Dehydro-Aripiprazole	AUC t (n=16,17)	1990 ng day/mL	Standard Deviation 603

Primary

Maximum Observed Plasma Concentration (Cmax) of Aripriprazole

Relative bioavailability (Frel) of aripiprazole intramuscular (IM) depot injected in the deltoid muscle compared to the gluteal muscle based on aripiprazole maximum (peak) plasma concentrations (Cmax) PK parameter.

Time frame: Day 1: 4 hr, 8 hr, and 12 hr post dose, Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112 and 126/Early termination

Population: The dataset for the PK analysis consisted of all dosed subjects who had evaluable aripiprazole and dehydro-aripiprazole PK parameters.

Arm	Measure	Value (MEAN)	Dispersion
Aripiprazole IM Depot 400 mg: Deltoid	Maximum Observed Plasma Concentration (Cmax) of Aripriprazole	170 ng/mL	Standard Deviation 58.6
Aripiprazole IM Depot 400 mg: Gluteal	Maximum Observed Plasma Concentration (Cmax) of Aripriprazole	136 ng/mL	Standard Deviation 70.3

Primary

Maximum Observed Plasma Concentration (Cmax) of Dehydro-Aripiprazole

Time frame: Day 1: 4 hr, 8 hr, and 12 hr post dose, Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112 and 126/Early termination

Population: The dataset for the PK analysis consisted of all dosed subjects who had evaluable aripiprazole and dehydro-aripiprazole PK parameters.

Arm	Measure	Value (MEAN)	Dispersion
Aripiprazole IM Depot 400 mg: Deltoid	Maximum Observed Plasma Concentration (Cmax) of Dehydro-Aripiprazole	51.7 ng/mL	Standard Deviation 23.3
Aripiprazole IM Depot 400 mg: Gluteal	Maximum Observed Plasma Concentration (Cmax) of Dehydro-Aripiprazole	34.6 ng/mL	Standard Deviation 13.2

Secondary

Number of Participants Reporting Treatment Emergent Adverse Events (TEAE).

Safety was measured according to standard adverse event collection as described in the adverse event section of the results.

Time frame: Starting at the time the ICF was signed to Day 126/Early termination