Clinical Trials Register

Summary
EudraCT Number:	2010-023816-15
Sponsor's Protocol Code Number:	D4131C00001
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-02-11
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

Finland - Fimea

A.2

EudraCT number

2010-023816-15

A.3

Full title of the trial

A Phase IIb, Randomized, Double-Blind, Placebo-Controlled, Active
Controlled, Parallel Group, Multicenter Study to Assess the Safety and
Efficacy of 2 Fixed Dose Groups of TC-5214 (S-mecamylamine) as
Monotherapy Treatment in Patients with Major Depressive Disorder with
an Inadequate Response to Antidepressant Therapy

A.3.1

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

A study to assess the safety and effect of TC-5214 in patients with major depressive disorder.

A.4.1

Sponsor's protocol code number

D4131C00001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01288079

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	AstraZeneca AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Targacept, Inc
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	AstraZeneca
B.5.2	Functional name of contact point	Information Centre
B.5.3	Address:
B.5.3.1	Street Address	-
B.5.3.2	Town/ city	-
B.5.3.3	Post code	-
B.5.3.4	Country	United States
B.5.4	Telephone number	001800236 9933
B.5.5	Fax number	---
B.5.6	E-mail	information.center@astrazeneca.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	TC-5214 (S-mecamylamine)
D.3.2	Product code	TC-5214 (S-mecamylamine)
D.3.4	Pharmaceutical form	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.3.9.1	CAS number	107596-30-5
D.3.9.2	Current sponsor code	TC-5214-23
D.3.9.3	Other descriptive name	S(+)-Mecamylamine
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	1
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	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	TC-5214 (S-mecamylamine)
D.3.2	Product code	TC-5214 (S-mecamylamine)
D.3.4	Pharmaceutical form	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.3.9.1	CAS number	107596-30-5
D.3.9.2	Current sponsor code	TC-5214-23
D.3.9.3	Other descriptive name	S(+)-Mecamylamine
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.IMP: 3
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	Cymbalta
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Gastro-resistant capsule, hard
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	DULOXETINE HYDROCHLORIDE
D.3.9.1	CAS number	136434-34-9
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	30
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	Tablet
D.8.4	Route of administration of the placebo	Oral 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

Patients with Major Depressive Disorder with an Inadequate Response to Antidepressant Therapy.

E.1.1.1

Medical condition in easily understood language

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10025453
E.1.2	Term	Major depressive disorder NOS
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 TC-5214 compared with placebo in patients with major depressive disorder (MDD) who exhibit an inadequate response to SSRI/SNRI therapy, as assessed by change in MADRS total score from Week 8 (baseline) to end of treatment (Week 16).

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of TC-5214 compared with placebo in patients with MDD
who exhibit an inadequate response to SSRI/SNRI therapy as assessed by
depressive symptoms, clinical global outcome regarding severity and improvement and anxiety.
• To evaluate the efficacy of TC-5214 compared with placebo in patients with MDD who exhibit an inadequate response to SSRI/SNRI therapy as assessed by patient reported outcomes (PROs) regarding functional impairment.
• To investigate pharmacokinetic (PK) properties of TC-5214 in patients with MDD using a population PK analysis methodology. SSRI/SNRI compliance will be
quantified in the open-label period. The PK properties of TC-5214 using
population PK analysis methodology will be investigated and reported separately
from the Clinical Study Report (CSR).

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

Pharmacogenetics Research. Version 1.0, date 11 Nov 2010

AstraZeneca intends to perform genetic research in the TC5214 clinical development programme to explore how genetic variations may affect the clinical parameters associated with TC 5214 and/or agents used in combination or as comparators. Collection of DNA samples from populations with well described clinical characteristics may lead to improvements in the design and interpretation of clinical trials and, possibly, to genetically guided treatment strategies. Studies may also be performed on the underlying genetic contribution to MDD.
The objective of this research is to collect and store DNA for future exploratory research into genes/genetic variation that may influence response (ie, distribution, safety, tolerability and efficacy) to TC 5214 and/or agents used in combination and/or as comparators. Investigations into the genetic factors influencing disease (depression) may also be undertaken.

E.3

Principal inclusion criteria

1. Provision oof signed and dated informed consent before initiation of any study related procedures. 2. Male or female patients aged 18 to 65 years, inclusive. 3. The patient must have a clinical diagnosis of major depressive disorder (MDD) with inadequate response to no more than one antidepressant.
4. Women of child-bearing potential must have a negative urine pregnancy test and confirmed use of a highly effective form of birth control before enrollment and until 3 months after their last dose of study drug. 5. Outpatient status at enrollment and randomization.

E.4

Principal exclusion criteria

1. Patients with a lifetime history of bipolar disorders; psychotic disorder or post-traumatic stress disorder.
2. Patients with a history of suicide attempts in the past year and/or seen by the investigator as having a significant history of risk of suicide or homicide.
3. Patients with any significant unstable hepatic, renal, pulmonary, cardiovascular, ophthalmologic, neurologic, or any other medical conditions that might confound the study or put the patient at greater risk during study participation. 4. History of stroke or transient ischemic attack, seizures or seizure disorder, head trauma including closed head injury. 5. Pregnancy or lactation.

E.5 End points

E.5.1

Primary end point(s)

Primary outcome measures: Change in the MADRS total score from randomization(Week 8) to end of treatment (Week 16).

E.5.1.1

Timepoint(s) of evaluation of this end point

Will be scored at Weeks 8 (baseline), 9, 10, 12, 14, 16.

E.5.2

Secondary end point(s)

1. Changes in clinician rated symptoms as assessed by MADRS, Hamilton Rating Scale for Depression (HAMD), Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I) and Hamilton Anxiety Assessment (HAM-A).

2. Changes in patient-reported outcomes as assessed by Sheehan Disability Scale (SDS), European Quality of Life (EQ-5D).

3. AE’s (any incidence) and SAE’s, will be assessed as a measure of safety and tolerability.

4. Change in physical exam results, vital signs, laboratory tests, ECG (electrocardiogram), and C-SSRS (Columbia Suicide Severity Rating Scale), CSFQ (Changes Sexual Functioning Questionnaire) and DESS (Discontinuation Emergent Signs and Symptoms) will be assessed as a measure of safety and tolerability.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. MADRS and CGI will be scored at Weeks 8 (baseline), 9, 10, 12, 14, 16.
HAM-D scored at weeks 8 (baseline), 12, and 16. HAM-A scored at weeks 8 (baseline) and 16.

2. SDS and EQ-5D will be scored at weeks 8 (baseline) and 16.

3. Collected weekly from the beginning of the screening period through Week 18. Unsolicited SAE’s will be collected from 30 days post last study treatment.

4. Routine safety monitoring from consent to withdrawal.

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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)

Yes

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

Estonia

Finland

India

Japan

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

The end of the study is defined as “the last visit of the last patient undergoing the study”. The end of study definition is for the entire study.

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:

352

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2011-02-11.

Yes

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

F.4.2.2

In the whole clinical trial

352

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)

As per normal treatment

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

2011-04-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-04-06

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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