| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adjunct treatment to an antidepressant in patients with Major Depressive Disorder who exhibit an inadequate response to antidepressant therapy |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025453 |
| E.1.2 | Term | Major depressive disorder NOS |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of TC-5214 compared with placebo as an adjunct to antidepressant (SSRI/SNRI) therapy in patients with MDD who exhibit an inadequate response to antidepressant therapy, as assessed by change in MADRS total score from randomization (Week 8) to end of treatment (Week 16).
Safety Objectives:
To evaluate the safety and tolerability of TC-5214 and placebo as an adjunct to an
antidepressant (SSRI/SNRI) in patients with MDD who exhibit an inadequate response to antidepressant therapy. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of TC-5214 compared with placebo as an adjunct to an antidepressant (SSRI/SNRI) in patients with MDD who exhibit an inadequate response to antidepressant therapy as assessed by depressive symptoms, clinical global outcome regarding severity and improvement, and anxiety, and as assessed by patient-reported outcomes (PROs) regarding functional impairment, overall quality of life, and severity of depressive symptoms.
To investigate pharmacokinetic (PK) properties of TC-5214 in patients with MDD
using a population PK analysis methodology. SSRI/SNRI will be quantified in the
open-label ADT period. These results will be reported separately from the primary
and other secondary objectives.
Change in overall quality of life and satisfaction from randomization (Week 8) to
end of treatment in Q-LES-Q-SF, items 15 and 16.
Change in health-related quality of life as measured by the EuroQol VAS and
5 dimensions (EQ-5D) from randomization to end 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 |
Pharmacogenetics Research, appendix version 1.0, dated 4 May 2010
AstraZeneca intends to perform genetic research in the TC-5214 clinical development
program 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 co-medication. Investigations into the genetic factors influencing disease (depression) may also be undertaken.
|
|
| E.3 | Principal inclusion criteria |
1. Provision of signed and dated informed consent before initiation of any studyrelated
procedures.
2. Patients must provide acceptable proof of identity documentation to confirm initials
and date of birth.
3. Male or female patients aged 18-65 years, inclusive:
• Male patients: Male patients who are sexually active must use a double
barrier method of contraception (condom with spermicide) from the first dose
of IP until 12 weeks after their last dose.
• Women of childbearing potential: Women of child-bearing potential
(WOCBP) must have a negative urine pregnancy test and confirmed (by the
investigator) use of a highly effective form of birth control for 3 months before
enrollment and until 3 months after their last dose of IP. The following
methods of highly effective birth control include the birth control option plus
the use of a condom by the male sexual partner: vasectomized sexual partner,
tubal occlusion, intrauterine device (IUD [copper banded coils only]),
intrauterine system (eg, Mirena), Depo-Provera, implants (Implanon, Norplant), normal and low dose combined oral pills, ethinylestradiol
transdermal system (Evra Patch), and intravaginal device (NuvaRing). Highly
effective birth control can also include true sexual abstinence (starting at the
screening visit and through completion of the study). The investigator will
assess the method of birth control and compliance at each study visit.
• Women of non-child-bearing potential. Women of non child-bearing
potential are defined as women who are either permanently sterilized
(hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but
excluding bilateral tubal occlusion) or who are postmenopausal. Women will
be considered postmenopausal if they are amenorrheic for 12 months without
an alternative medical cause. The following age-specific requirements apply:
• Women under 50 years old would be considered post menopausal if they
have been amenorrheic for 12 months or more following cessation of
exogenous hormonal treatment and luteinizing hormone (LH) and
follicle stimulating hormone (FSH) levels in the post-menopausal range.
• Women over 50 years of age would be considered postmenopausal if
they have been amenorrheic for 12 months or more following cessation
of all exogenous hormonal treatment.
4. Primary clinical diagnosis meeting criteria from the DSM-IV-TR:
• 296.2x Major Depressive Disorder (MDD), Single Episode, Unspecified or
• 296.3x Major Depressive Disorder (MDD), Recurrent, Unspecified
as confirmed via the Mini International Neuropsychiatric Interview (MINI)
version.6.0 diagnostic scale.
5. History during current depressive episode of an inadequate response to no more
than one antidepressant (SSRI/SNRI) as assessed by a review of the patients history
(ATHF). Patients who are not currently receiving treatment with antidepressant
drugs during this current depressive episode are allowed.
6. Documented HAMD-17 as follows:
− Screening (Visit 1) and open-label baseline (Visit 2): Clinician-rated total
score ≥20.
− Randomization (Week 8/Visit 6): Clinician rated ≥16 total score and a <50%
reduction in total score compared to open-label baseline (Visit 2).
7. Have a HAMD-17 score ≥2 on item 1 (depressed mood) at screening (Visit 1) and
open-label baseline (Visit 2).
8. Documented CGI-S as follows:
− Screening (Visit 1): CGI -S score ≥4
− Randomization (Week 8/Visit 6): CGI-S score ≥4
9. Be able to understand and comply with the requirements of the study, as judged by the investigator.
10. Outpatient status at enrollment and randomization (Week 8) other than social
hospitalization as locally allowed.
For inclusion into the optional exploratory genetic sample collection, patients must fulfill the following additional criterion:
11. Have provided written informed consent for genetic sampling before initiation of
any genetic sampling.
If a patient declines to participate in the optional genetic portion of the study, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this CSP, so long as they consent. |
|
| E.4 | Principal exclusion criteria |
1. Patients with: a) lifetime history of bipolar disorder and/or psychotic disorder; MDD
with psychotic features is excluded; b) current (within 12 months before open-label
baseline [Visit 2]) manic episode, post-traumatic stress disorder as assessed by the
MINI 6.0 and confirmed by the investigator; c) current (within 12 months before
open-label baseline [Visit 2]) generalized anxiety disorder, panic disorder, obsessive
compulsive disorder or social anxiety disorder as assessed by the MINI 6.0, and
considered by the investigator to be primary (causing a higher degree of distress or
impairment than MDD).
2. Patients with a diagnosis of DSM-IV-TR Axis II disorder which has a major impact
on the patient’s current psychiatric status.
3. Patients whose current episode of depression started less than 8 weeks before
screening.
4. History of hypersensitivity or intolerance to drugs with a similar chemical structure
or class to TC-5214.
5. Substance or alcohol abuse or dependence within 6 months prior to enrollment, as defined in DSM-IV-TR criteria. Patients with a positive urine toxicology screen will be excluded, with the exception of patients testing positive for cannabinoids.
6. Subjects 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, or
considered at risk for suicide or homicide during the study. Also patients who have
a HAMD-17 item 3 score of ≥3.
7. Presence of renal insufficiency as evidenced by creatinine clearance of ≤50 mL/min
8. 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.
9. Positive test results for human immunodeficiency virus antibody.
10. History of renal insufficiency or impairment or conditions that could affect
absorption or metabolism of investigational product
11. Patients on thyroid medication unless at a stable dose for ≥3 months; thyroid level must be within normal range.
12. A diagnosis of cancer (except basal or squamous cell skin carcinoma), unless in
remission for at least 5 years.
13. Any other severe progressive or uncontrolled medical condition, or chronic medical illness.
14. Known presence of raised intraocular pressure or history of narrow-angle glaucoma.
15. Evidence of uncontrolled diabetes mellitus as judged by the investigator or exhibited by hemoglobin A1c >8%.
16. Alanine aminotransferase or asparate aminotransferase ≥3.0 times the upper limit of normal and total bilirubin 1.2 times the ULN.
17. History of severe medication allergy/hypersensitivity or ongoing medication
allergy/hypersensitivity
18. History of stroke or transient ischemic attack.
19. Myocardial infarction within 180 days before screening (Visit 1).
20. History of seizures or seizure disorder (single infant febrile seizure with full
recovery is acceptable).
21. History of head trauma, including closed head injury, in which loss of consciousness occurred.
22. Receipt of electroconvulsive therapy within the last 2 years.
23. Use of prohibited treatments.
24. Patients who, in the investigator’s opinion, will require any form of psychotherapy
during the study period, unless psychotherapy has been ongoing for a minimum of
3 months prior to study start.
25. Pregnancy or lactation.
26. Clinically significant deviation from the reference range in clinical laboratory test
results at enrollment, as judged by the investigator.
27. Donation of plasma or blood products within 14 days of Day 1.
28. History of orthostatic hypotension.
29. Clinically significant electrocardiogram abnormalities as determined by the
investigator and/or central ECG reader.
30. QTcF (Fridericia-corrected) ≥450 msec (on repeated tests) at screening (Visit 1) or randomization (Visit 6) and medical history or family history of long QT syndrome.
31. Involvement in the planning and/or conduct of this study.
32. Previous randomization in this study.
33. Patients who previously received TC-5214 (S-mecamylamine) or Inversine®.
34. Randomization in another clinical trial currently or within 3 months of screening or
participation in more than 2 trials in the 12 months prior to screening.
35. Judgment by the investigator that the patient should not participate in the study if he/she considers patient unlikely to comply with study procedures, restrictions, and
requirements.
In addition, the following are considered criteria for exclusion from the genetic research:
36. Have had previous allogeneic bone marrow transplant.
37. Received non-leukocyte depleted whole blood transfusion in the 120-day period
preceding the date of genetic sample collection. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary efficacy variable: Change in the MADRS total score from randomization (Week 8) to end of treatment (Week 16). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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