A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Phase III, Efficacy and Safety Study of 3 Fixed Dose Groups of TC-5214 (S-mecamylamine) as an Adjunct to an Antidepressant in Patients with Major Depressive Disorder Who Exhibit an Inadequate Response to Antidepressant Therapy

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2010-024137-22-HU
• Date of registration: 15/02/2011
• Prospective Registration: No
• Primary sponsor: AstraZeneca AB
• Public title: A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Phase III, Efficacy and Safety Study of 3 Fixed Dose Groups of TC-5214 (S-mecamylamine) as an Adjunct to an Antidepressant in Patients with Major Depressive Disorder Who Exhibit an Inadequate Response to Antidepressant Therapy
• Scientific title: A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Phase III, Efficacy and Safety Study of 3 Fixed Dose Groups of TC-5214 (S-mecamylamine) as an Adjunct to an Antidepressant in Patients with Major Depressive Disorder Who Exhibit an Inadequate Response to Antidepressant Therapy
• Date of first enrolment: 11/02/2011
• Target sample size: 795
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-024137-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Hungary

Key inclusion & exclusion criteria

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 inv
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 medic

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Adjunct treatment to an antidepressant in patients with Major Depressive Disorder who exhibit an inadequate response to antidepressant therapy
MedDRA version: 12.1 Level: LLT Classification code 10025453 Term: Major depressive disorder NOS

Intervention(s)

Product Name: TC-5214 (S-mecamylamine)
Product Code: TC-5214 (S-mecamylamine)
Pharmaceutical Form: Tablet
CAS Number: 107596-30-5
Current Sponsor code: TC-5214-23
Other descriptive name: S(+)- Mecamylamine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: TC-5214 (S-mecamylamine)
Product Code: TC-5214 (S-mecamylamine)
Pharmaceutical Form: Tablet
CAS Number: 107596-30-5
Current Sponsor code: TC-5214-23
Other descriptive name: S(+)-Mecamylamine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: TC-5214 (S-mecamylamine)
Product Code: TC-5214 (S-mecamylamine)
Pharmaceutical Form: Tablet
CAS Number: 107596-30-5
Current Sponsor code: TC-5214-23
Other descriptive name: S(+)-Mecamylamine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: 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 1) depressive symptoms, clinical
global outcome regarding severity and improvement, and anxiety, 2) by patient-reported outcomes (PROs) regarding functional impairment, overall quality of life, severity of depressive symptoms, and irritability 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)

Primary end point(s): Primary efficacy variable: Change in the MADRS total score from randomization (week8) to end of treatment (week16)

Main Objective: 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 and tolerability 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.

Secondary ID(s)

D4130C00004