Clinical Trials Register

Summary
EudraCT Number:	2017-002317-58
Sponsor's Protocol Code Number:	ITI-007-404
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-01-25
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2017-002317-58

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy
and Safety of Lumateperone Monotherapy in the Treatment of Patients with Major Depressive Episodes Associated with Bipolar I or Bipolar II Disorder (Bipolar Depression) Conducted Globally

A.3.1

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

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy and Safety of Lumateperone Monotherapy in the Treatment of Patients with Major Depressive Episodes Associated with Bipolar I or Bipolar II Disorder (Bipolar Depression) Conducted Globally

A.3.2

Name or abbreviated title of the trial where available

ITI-007-404

A.4.1

Sponsor's protocol code number

ITI-007-404

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03249376

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	Intra-Cellular Therapies, Inc. (ITI)
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	Intra-Cellular Therapies, Inc. (ITI)
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	Intra-Cellular Therapies, Inc. (ITI)
B.5.2	Functional name of contact point	Program Manager
B.5.3	Address:
B.5.3.1	Street Address	Alexandria Center for Life Science, 430 East 29th Street, Suite 900
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	10016 USA
B.5.3.4	Country	United States
B.5.4	Telephone number	+1-858-692-6690
B.5.6	E-mail	smaino@intracellulartherapies.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	No
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.3.2	Product code	ITI-007
D.3.4	Pharmaceutical form	Capsule
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	Lumateperone Tosylate
D.3.9.1	CAS number	1187020-80-9
D.3.9.2	Current sponsor code	ITI-007 tosylate
D.3.9.3	Other descriptive name	ITI-007, FP-212, IC200056 tosylate salt, ITI-11-tosylate
D.3.9.4	EV Substance Code	AS1
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	60
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	Capsule
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

Bipolar I or Bipolar II Disorder (Bipolar
Depression)

E.1.1.1

Medical condition in easily understood language

Bipolar Depression

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	10004936
E.1.2	Term	Bipolar depression
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

The primary objective of this study is to compare the efficacy of lumateperone administered orally once daily to that of placebo as measured by mean change from baseline to Day 43 in the total score on the rater-administered Montgomery-Åsberg Depression Rating Scale (MADRS) in patients with Bipolar Depression.

E.2.2

Secondary objectives of the trial

The efficacy secondary objectives of this study are to compare the efficacy of lumateperone administered orally once daily to that of placebo in relation to:
• MADRS - Time course of improvement:
o as measured by absolute mean change from
baseline in the MADRS total score at each assessment time point;
o as measured in days from first dose date to the
earliest date that a ≥50% decrease in the MADRS total score from baseline
is observed);
o as measured by the proportion of treatment
responders where response is defined as a ≥50% decrease in the MADRS
total score from baseline at each assessment time point, including at Study
Day 43;
o as measured by the proportion of remitters
where remission is defined as a MADRS total score ≤12 at each assessment
time point, including at Study Day 43;

o The improvement in sleep, as measured by Item 4 (reduced sleep) on the
MADRS in patients with at least mild sleep disturba

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Is capable of understanding the written informed consent, provides signed and
witnessed written informed consent, and agrees to comply with protocol
requirements.
2. Is between the ages of 18 and 75 years, inclusive, at the start of screening (both
male and female patients are to be included).
3. Meets the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition
(DSM-5) criteria for Bipolar I or Bipolar II Disorder as confirmed by the
investigator or sponsor-approved expert site-based rater by a M.I.N.I.
International Neuropsychiatric Interview and meeting all of the following 5 criteria:
a. The start of the current MDE is at least 2 weeks but no more than
6 months prior to the screening visit;
b. Appropriate severity of illness, at least moderately ill, as measured by a
rater-administered MADRS total score ≥20 and corresponding to a CGIBP-
S score of ≥4 at the screening and baseline visits;
c. Sufficient history and/or independent report (such as family member or
outside practitioner) verifying that the current MDE is causing clinically
significant distress or impairment in social, occupational, or other
important areas of functioning;
d. A lifetime history of at least 1 Bipolar manic episode or mixed episode
(for Bipolar I) or hypomanic episode (for Bipolar II);
e. A rater-administered YMRS total score of ≤12 at the screening and
baseline visits.
4. Has a body mass index (BMI) of 19 – 35 kg/m2, inclusive.
5. Either must agree to use highly effective methods of birth control (defined as
those, alone or in combination, that result in a failure rate less than 1 percent per
year when used consistently and correctly) for at least 2 weeks prior to
randomization (starting with signing informed consent) through to the end-ofstudy
follow-up visit or must be of non-childbearing potential (defined as either
permanently sterilized or, if female, post-menopausal; the latter is defined as at
least 1 year with no menses without an alternative medical explanation).
6. In the opinion of the investigator, the patient is willing and able to comply with
study requirements, study visits, and to return to the clinic for follow-up
evaluations as specified by the protocol.

E.4

Principal exclusion criteria

1. The patient experiences a decrease in the rater-administered MADRS total score of ≥25% between screening and baseline visits.
2. In the opinion of the investigator, the patient has a significant risk for suicidal behavior during the course of his or her participation in the study
3. The patient is pregnant or breast-feeding; female patients of childbearing potential must have a negative urine pregnancy test at screening and on Day 1 prior to study treatment administration.
4. The patient has a history within 12 months of screening, based on previous psychiatric evaluation or a confirmed diagnosis upon screening based on the DSM-5, of a psychiatric diagnosis other than Bipolar Disorder, including:
a. Schizophrenia or other psychotic disorder;
b. Anxiety disorders such as panic disorder, general anxiety disorder, or
post-traumatic stress disorder as a primary diagnosis (however, anxiety
symptoms may be allowed, if secondary to Bipolar Disorder, provided
these symptoms do not require current treatment);
c. Feeding or eating disorder;
d. Primary diagnosis of obsessive compulsive disorder;
e. Personality disorder;
f. Moderate or severe substance use disorder (including for cannabis,
excluding for nicotine);
g. Any other psychiatric condition (other than Bipolar Disorder) that has been
the main focus of treatment within 12 months of screening.
5. Patients who have experienced hallucinations, delusions, or any other psychotic symptomatology in the current depressive episode may be allowed but should be reviewed with the on a case by case basis prior to inclusion.
6. The patient has been hospitalized for mania associated with Bipolar I Disorder within 30 days of screening.
7. The patient has received electroconvulsive therapy, vagal nerve stimulation, or repetitive trans-cranial magnetic stimulation within the last 5 years or received more than 1 course of electroconvulsive therapy during the patient’s lifetime.
8. The patient is considered a rapid cycler, defined by the occurrence of at least 6 major depressive, manic, hypomanic, or mixed episodes during the previous year. These episodes must be demarcated either by a partial or full remission of at least 2 months' duration or by a switch to an episode of opposite polarity.
9. The patient is considered treatment-resistant, defined as having a lifetime history
of treatment resistance (no remission) to ≥2 treatments with medications
approved by the regional regulatory authority for Bipolar Depression at an adequate dose (per regulatory approved label) for an adequate duration (at least 6 weeks).
10.The patient is currently receiving formal cognitive or behavioral therapy,
systematic psychotherapy, or plans to initiate such therapy during the study.
11.The patient presents with a lifetime history of epilepsy, seizure or convulsion, or electroencephalogram with clinically significant abnormalities, delirium, dementia, amnestic, or other cognitive disorder or significant brain trauma.
12. The patient has a positive test for drugs of abuse or alcohol at the screening visit, or presents evidence of either withdrawal from or acute intoxication with cocaine, opiates, amphetamines (including methamphetamine), alcohol, barbiturates, or hallucinogens or similar compounds.
13. The patient has used 1 of the following agents under the specified conditions:
a. Lifetime exposure to ITI-007 (i.e., participated in previous clinical study with ITI-007) or who has had exposure to any investigational product within 3 months of the baseline visit or participated in the past 4 years in >2 clinical studies of an investigational product with a central nervous system indication;
b. Any strong or moderate cytochrome P450 3A4 inhibitor or inducer within 7 days prior to the baseline visit;
c. Use of any short-acting anxiolytic medications within 1 week of the baseline visit or of long-acting anxiolytics within 5 half-lives of the baseline visit;
d. Drugs with known psychotropic properties or any non-psychotropic drugs with known or potentially significant central nervous system effects within the last 28 days or 5 half-lives before the baseline visit
14. The patient has abnormal laboratory values or clinical findings at screening
15. The patient has clinically significant cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurological, malignancy, pheochromocytoma, metabolic, psychiatric or other condition that might be detrimental to the patient if he or she participates in the study
16. The patient has a history of human immunodeficiency virus (HIV) infection or Hepatitis B or C
17. The patient is unable to be safely discontinued from current antidepressant medication, mood stabilizers, anticholinergics, or other psychotropic medications

E.5 End points

E.5.1

Primary end point(s)

The change from baseline to Day 43 in MADRS total score is the primary outcome measure for the study.

E.5.1.1

Timepoint(s) of evaluation of this end point

Change from baseline to Day 43 in the MADRS total score.

E.5.2

Secondary end point(s)

The secondary efficacy outcome measures include change from baseline in the MADRS, CGI-BP-S, and the Q-LES-Q-SF.
The secondary safety outcome measures include AEs, YMRS, C-SSRS, AIMS, BARS, SAS, clinical laboratory evaluations, ECGs, vital signs, and physical exams and neurological findings.
The pharmacokinetic measures will include the assessment of plasma levels of ITI-007 and metabolites.

E.5.2.1

Timepoint(s) of evaluation of this end point

Change from baseline to Day 43 in the CGI-BP-S score.
Safety measures will be collected at each visit.
Pk samples will be taken on Days 8, 43 and follow-up.

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

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

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

Yes

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

Colombia

Mexico

Poland

Romania

Russian Federation

Serbia

Ukraine

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

LVLS

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