Trial Outcomes & Findings for Trial Evaluating OPC-34712 in Subjects With Normal Renal Function and Renally Impaired Subjects (NCT NCT01289080)

NCT ID: NCT01289080

Last Updated: 2015-10-29

Results Overview

Blood samples were collected on Day 1 at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours Postdose or at Early Termination (ET). Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 19 participants
• Primary outcome timeframe: Day 1 to Day 8
• Results posted on: 2015-10-29

Participant Flow

The trial was an open-label, multicenter, parallel-arm, single-dose trial in two groups: 1 group of participants with normal renal function and 1 group of severely renally impaired participants.

The participant assignment was made based on Urine Creatinine Clearance (urine CLcr). If the urine CLcr was < 30 mL/minute for renally impaired participants and the urine CLcr was > 80 mL/minute for participants with normal renal function.

Participant milestones

Measure	Normal Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Overall Study STARTED	9	10
Overall Study COMPLETED	9	10
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Trial Evaluating OPC-34712 in Subjects With Normal Renal Function and Renally Impaired Subjects

Baseline characteristics by cohort

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=10 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.	Total n=19 Participants Total of all reporting groups
Age, Continuous	58.8 Years STANDARD_DEVIATION 10.1 • n=5 Participants	62.9 Years STANDARD_DEVIATION 12.2 • n=7 Participants	60.9 Years STANDARD_DEVIATION 11.1 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for pharmacokinetics (PK) analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Blood samples were collected on Day 1 at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours Postdose or at Early Termination (ET). Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

Outcome measures

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=10 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Unbound Area Under the Concentration (AUC) Time Curve Calculated to the Last Observable Concentration Brexpiprazole (AUCt,u).	8.17 nanograms*hours/mL (ng*h/mL) Standard Deviation 1.37	13.3 nanograms*hours/mL (ng*h/mL) Standard Deviation 6.26

PRIMARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Blood samples were collected at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours or at ET. Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

Outcome measures

Measure	Normal n=7 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=7 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Unbound Area Under AUC- Time Curve From Time Zero to Infinity (AUC∞,u).	9.58 ng*h/mL Standard Deviation 2.26	18.0 ng*h/mL Standard Deviation 8.72

PRIMARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Blood samples were collected at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours or at ET. Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

Outcome measures

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=10 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Unbound Maximum (Peak) Plasma Concentration of Brexpiprazole (Cmax,u).	0.195 ng/mL Standard Deviation 0.0662	0.198 ng/mL Standard Deviation 0.0702

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Blood samples were collected at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours or at ET. The AUCt was estimated using the linear trapezoidal rule.

Outcome measures

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=9 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
AUC Time Curve of Brexpiprazole Metabolite (DM-3411) Calculated to the Last Observable Concentration at Time t (AUCt).	1410 ng*h/mL Standard Deviation 423	2080 ng*h/mL Standard Deviation 1230

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations. AUC-time curve from zero to infinity (AUC∞) was not determined for DM-3411 metabolite.

Blood samples were collected at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours or at ET. The AUC∞ was estimated using the linear trapezoidal rule.

Outcome measures

Measure	Normal n=7 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=7 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
AUC Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞).	2050 ng*h/mL Standard Deviation 510	3800 ng*h/mL Standard Deviation 1970

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Blood samples were collected at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours or at ET. Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

Outcome measures

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=10 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Maximum Plasma Concentration of Brexpiprazole Metabolite (DM-3411) (Cmax).	18.2 ng/mL Standard Deviation 6.24	19.8 ng/mL Standard Deviation 12.3

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Blood samples were collected at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours or at ET. Tmax is the time taken to reach highest measured concentration of the drug during the dosing interval.

Outcome measures

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=10 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Time to Cmax of Brexiprazole Metabolite (DM-3411) (Tmax).	12.0 h Full Range 1.00-8.00 • Interval 8.0 to 24.0	30.0 h Full Range 2.00-8.00 • Interval 3.0 to 144.0

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

The value of CL/F was determined as Dose/AUC∞. Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) was influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the blood.

Outcome measures

Measure	Normal n=7 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=7 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Apparent Clearance From Plasma After Extravascular Administration of Brexpiprazole (CL/F).	23.0 mL/h/kg Standard Deviation 8.05	14.2 mL/h/kg Standard Deviation 6.46

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Blood samples were collected at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours or at ET. Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

Outcome measures

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=10 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Unbound Fraction of Brexpiprazole in Plasma (fu).	0.476 % of unbound brexpiprazole in plasma Standard Deviation 0.0525	0.492 % of unbound brexpiprazole in plasma Standard Deviation 0.0346

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Blood samples were collected at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours or at ET. Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

Outcome measures

Measure	Normal n=7 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=7 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Apparent Unbound Clearance From Plasma After Extravascular Administration of Brexpiprazole (CLu/F).	0.110 mL/h/kg Standard Deviation 0.0493	0.0686 mL/h/kg Standard Deviation 0.0336

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations. The terminal phase elimination half-life was not determined for DM-3411 metabolite.

Blood samples were collected at Predose (within 15 minutes of dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours or at ET. Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

Outcome measures

Measure	Normal n=7 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=7 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z).	71.7 h Standard Deviation 23.8	87.4 h Standard Deviation 28.9

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Urine samples were collected at Predose at intervals of 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

Outcome measures

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=9 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Renal Clearance (CLr) of Brexipiprazole Metabolite (DM-3411).	1.38 mL/h/kg Standard Deviation 0.883	0.683 mL/h/kg Standard Deviation 0.471

SECONDARY outcome

Timeframe: Day 1 to Day 8

Population: The dataset for PK analysis of all evaluable brexpiprazole PK parameters consisted of enrolled participants who had evaluable plasma concentrations.

Urine samples were collected at Predose and at intervals of 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. Unbound fraction of drug in plasma was calculated as 100% - mean percent of brexpiprazole bound to plasma protein for each participant.

Outcome measures

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=9 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
Fraction of the Systemically Available Brexpiprazole Metabolite (DM-3411) Excreted Into the Urine (fe,u).	3.91 % of unbound brexpiprazole in urine. Standard Deviation 1.66	2.55 % of unbound brexpiprazole in urine. Standard Deviation 1.19

SECONDARY outcome

Timeframe: AEs were recorded from Screening (ICF was signed) to Follow-up 31 (+ 2) days.

Population: The dataset for all safety analyses consisted of the data from all enrolled participants who received at least 1 dose of study medication, regardless of any protocol deviation. All observed data for these subjects were included.

An adverse event (AE) was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.

Outcome measures

Measure	Normal n=9 Participants Participants with normal renal function were administered 3 mg brexpiprazole on Day 1.	Renally Impaired n=10 Participants Participants with severe renal impairment were administered 3 mg brexpiprazole on Day 1.
The Abnormalities Found in Vital Signs, ECGs, and Clinical Laboratory Tests Are Reported as AEs Upon Study Physicians Discretion. Participants with adverse events	3 participants	5 participants
The Abnormalities Found in Vital Signs, ECGs, and Clinical Laboratory Tests Are Reported as AEs Upon Study Physicians Discretion. Participants with TEAEs	3 participants	5 participants
The Abnormalities Found in Vital Signs, ECGs, and Clinical Laboratory Tests Are Reported as AEs Upon Study Physicians Discretion. Participants with severe TEAEs	0 participants	1 participants

Adverse Events

Brexpiprazole 3mg

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Brexpiprazole 3mg n=19 participants at risk Participants with normal renal function and severe renal impairment were administered 3 mg brexpiprazole.
Gastrointestinal disorders Constipation	5.3% 1/19 • AEs were recorded from Screening (ICF was signed) to Follow-up 31 (+ 2) days. A SAE was any untoward medical occurrence that results in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Nervous system disorders Dizziness	5.3% 1/19 • AEs were recorded from Screening (ICF was signed) to Follow-up 31 (+ 2) days. A SAE was any untoward medical occurrence that results in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Nervous system disorders Headache	10.5% 2/19 • AEs were recorded from Screening (ICF was signed) to Follow-up 31 (+ 2) days. A SAE was any untoward medical occurrence that results in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Vascular disorders Hypotension	5.3% 1/19 • AEs were recorded from Screening (ICF was signed) to Follow-up 31 (+ 2) days. A SAE was any untoward medical occurrence that results in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Gastrointestinal disorders Nausea	5.3% 1/19 • AEs were recorded from Screening (ICF was signed) to Follow-up 31 (+ 2) days. A SAE was any untoward medical occurrence that results in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Vascular disorders Orthostatic hypotension	10.5% 2/19 • AEs were recorded from Screening (ICF was signed) to Follow-up 31 (+ 2) days. A SAE was any untoward medical occurrence that results in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Nervous system disorders Somnolence	15.8% 3/19 • AEs were recorded from Screening (ICF was signed) to Follow-up 31 (+ 2) days. A SAE was any untoward medical occurrence that results in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Infections and infestations Upper respiratory tract infection	5.3% 1/19 • AEs were recorded from Screening (ICF was signed) to Follow-up 31 (+ 2) days. A SAE was any untoward medical occurrence that results in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.

Additional Information

Global Medical Affairs

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Phone: 800 562-3974

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place