Clinical Trials Register

Summary
EudraCT Number:	2018-000063-88
Sponsor's Protocol Code Number:	RAP-MD-31
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-04-16
Trial 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

2018-000063-88

A.3

Full title of the trial

A Randomized, Double-blind, Placebo- and Active- controlled, Multicenter Study of Rapastinel as Monotherapy in Major Depressive Disorder

A.3.1

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

A Randomized, Double-blind, Placebo- and Active- controlled, Multicenter Study of Rapastinel as Monotherapy in Major Depressive Disorder

A.4.1

Sponsor's protocol code number

RAP-MD-31

A.5.4

Other Identifiers

Name:

IND

Number:

136,870

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	Allergan Ltd.
B.1.3.4	Country	United Kingdom
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	Allergan Sales LLC
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	Allergan Ltd.
B.5.2	Functional name of contact point	EU Global Clinical Trial Management
B.5.3	Address:
B.5.3.1	Street Address	Marlow International, The Parkway
B.5.3.2	Town/ city	Marlow, Buckinghamshire
B.5.3.3	Post code	SL7 1YL
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	44 1628494444
B.5.6	E-mail	ML-RAP-MD-31@allergan.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.3.1	Product name	rapastinel
D.3.2	Product code	AGN-241659 (previously GLYX-13)
D.3.4	Pharmaceutical form	Solution for infusion in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RAPASTINEL
D.3.9.4	EV Substance Code	SUB192215
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	75 to 150
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	Comparator
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	vortioxetine
D.2.1.1.2	Name of the Marketing Authorisation holder	H. Lundbeck A/S
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.3.1	Product name	vortioxetine
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	VORTIOXETINE
D.3.9.1	CAS number	508233-74-7
D.3.9.4	EV Substance Code	SUB88928
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 20
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	Solution for injection in pre-filled syringe
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
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

Major depressive disorder

E.1.1.1

Medical condition in easily understood language

Severe 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	PT
E.1.2	Classification code	10057840
E.1.2	Term	Major depression
E.1.2	System Organ Class	10037175 - Psychiatric disorders

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 evaluate the efficacy of rapastinel (450 mg IV) versus placebo and vortioxetine (10-20 mg oral) versus placebo in the treatment of MDD, as measured by the change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at end of treatment (end of week 6)

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of rapastinel (450 mg IV) versus placebo and vortioxetine (10-20 mg oral) versus placebo in the treatment of
MDD, as measured by the change from baseline MADRS total score at 1 day post-first dose of treatment

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

Pharmacogenetic
Blood samples may be collected at any time between Visits 2
and 9, inclusive, in support of pharmacogenetic biobanking
and analysis. Participation is optional.

Pharmacokinetic
Sparse pharmacokinetic (PK) samples will be taken from patients consenting to optional PK sampling to determine plasma concentrations of rapastinel using a validated bioanalytical method.

E.3

Principal inclusion criteria

●Male and female outpatients who are 18 to 75 years of age
●Meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for MDD (based on confirmation from the Structured Clinical Interview for Diagnostic Statistic Manual of Mental
Health Disorders, Fifth Edition [SCID]), with a current major depressive episode of at least 8 weeks and not exceeding 18 months in duration at Visit 1
●Have a minimum score of 26 on the rater-administered Montgomery-Åsberg Depression Rating Scale (MADRS) and a minimum score of 24 on the computer administered MADRS at screening (Visit 1) and baseline (Visit 2)
●Have a Clinical Global Impressions - Severity (CGI-S) score of ≥ 4 at screening and baseline
●Inadequate response (< 50% reduction in depressive symptoms) to 1 to 3 antidepressant therapies [ADTs] given at adequate doses (as defined by the ADT package insert) and duration of ≥ 4 weeks during the present episode as documented using the Antidepressant
Treatment Response Questionnaire [ATRQ]

E.4

Principal exclusion criteria

●DSM-5–based diagnosis of any disorder other than MDD that was the primary focus of treatment within 6 months before Visit 1. Comorbid generalized anxiety disorder, social anxiety disorder, or specific phobias are acceptable provided they play a secondary role in the balance of symptoms and are not the primary driver of treatment
decisions.
● Lifetime history of meeting DSM-5 criteria for:
a. Schizophrenia spectrum or other psychotic disorder
b. Bipolar or related disorder
c. Major neurocognitive disorder
d. Neurodevelopmental disorder of greater than mild severity or of a severity that impacts the patient’s ability to consent, follow study directions, or otherwise safely participate in the study
e. Dissociative disorder
f. Posttraumatic stress disorder
g. MDD with psychotic features
●History of meeting DSM-5 criteria for alcohol or substance use disorder (other than nicotine or caffeine) within the 6 months before Visit 1
● DSM-5–based diagnosis of any personality disorder of sufficient severity to interfere with participation in this study in the opinion of the investigator
● History (based on patient report, medical records, and investigator judgement) of:
a. Inadequate response to electroconvulsive therapy (ECT), a monoamine oxidase inhibitor or ketamine
b. Treatment with clozapine or any depot antipsychotic (exception: episodic use of clozapine at doses ≤ 150 mg/day for the treatment of insomnia)
c. ECT, vagus nerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system treatment during the current episode or in the 6 months before Visit 1 (whichever is longer)
d. Tardive dyskinesia, serotonin syndrome, or neuroleptic malignant syndrome
e. Intolerance or hypersensitivity to rapastinel or vortioxetine
●Having received:
a. Anticonvulsant/mood stabilizer, within 1 year prior to Visit 1
b. Antipsychotic in the current episode, with the exception of quetiapine ≤ 50 mg/day or clozapine ≤ 150 mg/day given for insomnia provided it can be safely discontinued prior to Visit 2
c. Treatment with lithium as an ADT augmentation agent in the current episode
● Positive result at Visit 1 from the urine drug screen (UDS) test for any prohibited medication. Exception: patients with a positive UDS at Visit 1 for opiates, cannabinoids or episodic use of benzodiazepines may be allowed in the study provided:
a. The drug was used for a legitimate medical purpose (any recreational use is exclusionary);
b. The drug can be discontinued prior to participation in the study (except for episodic use of benzodiazepines which may be continued); and
c. A repeat UDS is negative for these substances prior to enrollment (except for episodic use of benzodiazepines which may be continued)
●Suicide risk, as determined by meeting any of the following criteria:
a. A suicide attempt within the past year
b. Significant risk, as judged by the investigator, based on the psychiatric interview or information collected in the C-SSRS at Visit 1 or Visit 2
c. MADRS Item 10 score ≥ 5 at Visit 1 or Visit 2 on either the rater administered MADRS or computer-administered MADRS
● At imminent risk of injuring self or others or causing significant damage to property, as judged by the investigator
●Requiring concomitant treatment with any of the prohibited medications, supplements, or herbal products, including any psychotropic drug or any drug with psychotropic activity.
● Prior participation in any investigational study of rapastinel/GLYX-13
●Initiation or termination of psychotherapy for depression within the 3 months preceding Visit 1, or plans to initiate, terminate, or change such therapy during the course of the study. (Support meetings or counseling [eg, marital counseling] are allowed provided they are no more frequent than weekly and do not have treatment of depression as their objective)
● Ongoing treatment with phototherapy, or termination of phototherapy within 1 month of Visit 1

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in MADRS total score at the end of the
DBTP (end of Week 6)

E.5.1.1

Timepoint(s) of evaluation of this end point

After 6 weeks of treatment

E.5.2

Secondary end point(s)

Key Secondary Endpoint
Change from baseline in MADRS total score at 1 day after first dose of treatment

Additional Endpoints
•Change from baseline in MADRS at 7 days after first dose of treatment
•Change from baseline in CGI-S at 1 and 7 days after first
dose of treatment, and end of treatment (end of Week 6)
•Rate of sustained responders during treatment
•Rate of responders at 1 and 7 days after first dose of treatment, and end of treatment (end of Week 6)
•Rate of sustained remitters during treatment
•Rate of remitters at 1 and 7 days after first dose of treatment, and end of treatment (end of Week 6)
•Time to first response
•Time to first sustained response
•Time to first remission
•Time to first sustained remission
•Change from baseline in Sheehan Disability Scale (SDS)
at end of treatment (end of Week 6)
•Change from baseline in Medication Satisfaction
Questionnaire (MSQ) at end of treatment (end of Week 6)

E.5.2.1

Timepoint(s) of evaluation of this end point

Key secondary endpoint:
Change from baseline in MADRS total score at 1 day after first dose of
investigational product (IP)

Additional endpoints:
At each visit and the final analysis will be done at the end of the study

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

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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

Yes

E.8.2.3.1

Comparator description

vortioxetine

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

Canada

Czech Republic

France

Germany

Italy

Russian Federation

Serbia

Spain

Sweden

Ukraine

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

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 months

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:

621

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

366

F.4.2.2

In the whole clinical trial

690

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)

After completing this study, all participants may have the option of continuing into the extension study with continued access to study drug provided the study is still open to enrollment. The study will be limited to a certain number of participants, so participation is not guaranteed.

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

2019-04-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-16

P. End of Trial
P.	End of Trial Status	Ongoing

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