| 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 |
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| 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 |
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| 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 (selective serotonin reuptake inhibitor [SSRI]/serotonin/norepinephrine reuptake inhibitor [SNRI]) therapy in patients with major depressive disorder (MDD) who exhibit an inadequate response to antidepressant therapy, as assessed by change in the Montgomery-Åsberg Depression Rating Scale (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.
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| 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 also 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. 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 (Week 16) 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 (Week 8) to end of treatment (Week 16)
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| 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. |
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| E.3 | Principal inclusion criteria |
1. Provision of signed and dated informed consent before initiation of any study-related procedures.
2. Patients must provide acceptable proof of identity documentation to confirm initials and date of birth.
3. Male or female patients 18 to 65 years of age:
· 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 genetic research portion of the study, the patient must fulfill the following additional criteria:
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.
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| E.4 | Principal exclusion criteria |
1. Patients with: a) lifetime history of bipolar disorder 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 (except dependence in full remission, and except for caffeine or nicotine dependence), 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 (see Section 6.4.5.3). Patients can be re-tested if the initial urine toxicology screen is positive, but should be excluded if the results are still positive at the second test.
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 (measured using Cockroft-Gault equation).
8. Any significant unstable hepatic (including Hepatitis B [HBV] and Hepatitis C [HCV]), renal, pulmonary, cardiovascular (including uncontrolled hypertension defined as higher than 160/100 mm Hg), 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 (HIV) antibody.
10. History of renal insufficiency or impairment or conditions that could affect absorption or metabolism of investigational product (eg, malabsorption syndrome, severe liver disease, history of gastric bypass, gastrointestinal motility disorder including chronic constipation, pyloric stenosis, or history or ileus), as judged by the investigator.
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 (eg. fibromyalgia, chronic pain conditions, obstructive sleep apnea).
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 (HbA1c) >8%.
16. Alanine aminotransferase (ALT) or asparate aminotransferase (AST) ≥3.0 times the upper limit of normal (ULN) and total bilirubin 1.2 times the ULN (unless documented Gilbert’s syndrome).
17. History of severe medication allergy/hypersensitivity or ongoing medication allergy/hypersensitivity other than seasonal allergies, as judged by the investigator.
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 (ECT) within the last 2 years.
23. Use of prohibited treatments (refer to Table 4 and Table 5for additional information on prohibited medications).
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. Blood or plasma donation will not be allowed from the screening visit through completion of the study (patients who completed double-blind treatment and 1-2 week follow-up are considered as completing the study).
28. History of orthostatic hypotension.
29. Clinically significant electrocardiogram (ECG) abnormalities as determined by the investigator and/or central ECG reader.
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| 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). |
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| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 86 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
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| 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. |
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| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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