Clinical Trials Register

Summary
EudraCT Number:	2017-002222-20
Sponsor's Protocol Code Number:	331-201-00080
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-11-14
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2017-002222-20

A.3

Full title of the trial

A Multicenter, Randomized, Double-blind Trial of Brexpiprazole versus Placebo for the Acute Treatment of Manic Episodes, With or Without Mixed Features, Associated With Bipolar I Disorder

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study investigating the efficacy, tolerability and safety of brexpiprazole for the acute treatment of manic episodes, with or without mixed features, in subjects with a diagnosis of bipolar I disorder

A.4.1

Sponsor's protocol code number

331-201-00080

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03259555

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Otsuka Pharmaceutical Development &
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.5.2	Functional name of contact point	Melody Chiles
B.5.3	Address:
B.5.3.1	Street Address	2440 Research Boulevard
B.5.3.2	Town/ city	Rockville, Maryland
B.5.3.3	Post code	20850
B.5.3.4	Country	United States
B.5.6	E-mail	Melody.TC-Chiles@otsuka-us.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Rexulti
D.2.1.1.2	Name of the Marketing Authorisation holder	Otsuka Pharmaceutical Development & Commercialization, Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Brexpiprazole
D.3.9.1	CAS number	913611-97-9
D.3.9.2	Current sponsor code	OPC-34712
D.3.9.3	Other descriptive name	BREXPIPRAZOLE
D.3.9.4	EV Substance Code	SUB91646
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Rexulti
D.2.1.1.2	Name of the Marketing Authorisation holder	Otsuka Pharmaceutical Development & Commercialization, Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BREXPIPRAZOLE
D.3.9.1	CAS number	913611-97-9
D.3.9.2	Current sponsor code	OPC-34712
D.3.9.3	Other descriptive name	BREXPIPRAZOLE
D.3.9.4	EV Substance Code	SUB91646
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Rexulti
D.2.1.1.2	Name of the Marketing Authorisation holder	Otsuka Pharmaceutical Development & Commercialization, Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BREXPIPRAZOLE
D.3.9.1	CAS number	913611-97-9
D.3.9.2	Current sponsor code	OPC-34712
D.3.9.3	Other descriptive name	BREXPIPRAZOLE
D.3.9.4	EV Substance Code	SUB91646
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of Manic Episodes Associated with Bipolar I Disorder

E.1.1.1

Medical condition in easily understood language

Bipolar I Disorder

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10068455
E.1.2	Term	Bipolar I disorder, hypomanic
E.1.2	System Organ Class	100000004873

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate the efficacy of brexpiprazole for the acute treatment of manic episodes, with or without mixed features, in subjects with a diagnosis of bipolar I disorder.

E.2.2

Secondary objectives of the trial

To demonstrate the safety and tolerability of brexpiprazole in this same population.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Banked Samples for Research of Treatment Response and Disease Understanding

E.3

Principal inclusion criteria

1. Male or female subjects, ages 18 to 65 years, inclusive, at the time of informed consent.
2. Subjects who are able to complete the consent process as required by IRB or IEC prior to the initiation of any protocol-required procedures.
3. Ability, in the opinion of the principal investigator, to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and discontinuation of prohibited medication; and to read and understand written word in order to be reliably rated on assessment scales.
4. Subjects with a DSM-5 diagnosis of bipolar I disorder displaying an acute manic episode with or without mixed features requiring hospitalization. Diagnosis confirmed by the MINI and a history of at least one previous manic episode with or without mixed features with manic symptoms of sufficient severity to require one of the following interventions: hospitalization or treatment with a mood stabilizer, or treatment with an antipsychotic agent. “Require” is defined as an intervention that occurred rather than one that was recommended.
5. YMRS score of ≥ 24 at screening and baseline.
6. Subjects who, in the investigator’s judgment, require treatment with an atypical antipsychotic medication for their bipolar I disorder.
7. Subjects willing to discontinue all prohibited medications to meet protocol-required washouts prior to and during the trial period.

E.4

Principal exclusion criteria

1. Sexually active male or WOCBP (women of childbearing potential) who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of IMP.
2. Females who are breastfeeding and/or who have a positive pregnancy test result prior to receiving trial medication.
3.Subjects considered unresponsive to clozapine or who are only responsive to cloazapine.
4. Subjects with a history of DSM-5 diagnosis other than bipolar I disorder, including schizophrenia, schizoaffective disorder, major depressive disorder, attention-deficit/hyperactivity disorder, delirium, dementia, amnestic, or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder. All other current diagnoses must be discussed with the medical monitor.
5. Subjects whose current manic episode has lasted for more than 4 weeks overall, or who have required hospitalization > 21 days for the current acute episode at the time of the screening visit, excluding hospitalization for psychosocial reasons.
6. Subject with manic symptoms better accounted for by another general medical condition or direct physiological effect of substance (eg. medication)
7. Subjects who have had electroconvulsive treatment within the past 2 months.
8. Subjects with a positive drug screen for cocaine or other illicit drugs
9. Abnormal laboratory test results, vital signs or ECG results, unless based on investigator's judgment the findings are not medically significant or would not affect the trial results.
10. Rapid cyclers with more than 6 episodes in previous year
11. Subjects with uncontrolled hypo/hyperthyroidism
12. Subjects with uncontrolled hypertension or symptomatic hypotension or orthostatic hypotension.
13. Subject with epilepsy or history of seizures
14. Subjects who participated in a clinical trial within the last 60 days or who participated in more than 2 clinical trials within the past year.
15. Use of psychotropic medications (other than benzodiazepines) within 7 days of the baseline YMRS.
16. Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders
17. Subjects who received brexpiprazole in any prior clinical trial or currently taking commercially available brexpiprazole (Rexulti®).

E.5 End points

E.5.1

Primary end point(s)

Change from baseline to Day 21 of the double-blind treatment phase in the YMRS Total Score

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline to Day 21

E.5.2

Secondary end point(s)

The key secondary endpoint is the change from baseline to Day 21 in the double-blind treatment period in Clinical Global Impression – Bipolar (CGI-BP) severity of illness score in mania.
Other secondary efficacy endpoints are as follows:
1. Change from baseline in YMRS Total Score for each trial visit during the double-blind treatment period other than the Day 21 visit; 2. Change from baseline in CGI-BP severity of illness score in mania for each trial visit during the double-blind treatment period other than the Day 21 visit; 3. CGI-BP change from preceding phase score in mania at each trial visit during the double-blind treatment period; 4. YMRS response rate for each trial visit during the double-blind treatment period, where response is defined as ≥ 50% reduction in YMRS Total Score from baseline or YMRS Total Score ≤ 12; 5. YMRS remission rate for each trial visit during the double-blind treatment period, where remission is defined as YMRS Total Score ≤ 12; 6. CGI-BP change from preceding phase response rate in mania for each trial visit during the double-blind treatment period, where response is defined as a CGI-BP change from preceding phase score in mania of 1 or 2 (very much improved or much improved) from baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline to Day 21

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Bulgaria

Poland

Serbia

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit of last subject.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

320

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

128

F.4.2.2

In the whole clinical trial

320

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subjects who complete all trial visits through the Day 21 visit may be offered entry into an optional open-label rollover trial. (Protocol code: 331-201-00083, EudraCT: 2017-002225-38 ). Subjects who do not enter the open-label rollover trial will revert to their normal standard of care.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-02-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-01-02

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