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Therapeutic Areas: Psychiatry/Psychology | Neurology | Family Medicine
Disease Category: Depression
Location: United States, IL
Depression Study. 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
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled, Phase III study of the efficacy and safety of 8 weeks of treatment with TC-5214 in fixed doses of 0.5, 2 and 4 mg twice daily (BID) as an adjunct to an antidepressant (SSRI/SNRI) in the treatment of patients with MDD with an inadequate response to an antidepressant (SSRI/SNRI) therapy. Following the screening, washout and open-label antidepressant treatment (ADT) periods, eligible patients will be randomized to 1 of the 4 treatment regimens and assigned in a 1:1:1:1 ratio.
For inclusion in the study, patients should fulfill the following criteria:
- Provision of signed and dated informed consent before initiation of any studyrelated procedures.
- Patients must provide acceptable proof of identity documentation to confirm initials and date of birth.
- Male or female patients aged 18-65 years,
Patient Inclusion Criteria:
- 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.
- 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.
- 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.
- Documented HAMD-17 as follows: - Screening (Visit 1) and open-label baseline (Visit 2): Clinician-rated total score =20; an interactive voice response system (IVRS) HAMD-17 assessment (completed by the patient) will be used to assess symptom severity and concordance with that of the HAMD-17 scored by the investigator. Approximately 25% of patients will be selected to undergo a secondary siteindependent remote rater interview. Concordance and agreement between the site interview and the secondary interview will be required for entry in the ADT portion of this study. The specific concordance, selection and agreement measures will be described in the Clinical Study Report. - Randomization (Week 8/Visit 6): Clinician rated =16 total score and a <50% reduction in total score compared to open-label baseline (Visit 2).
- 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.
- Outpatient status at enrollment and randomization (Week 8). For inclusion into the optional exploratory genetic sample collection, patients must fulfill the following additional criterion:
- 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.
Patient Exclusion Criteria:
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
- Patients with:
- lifetime history of bipolar disorder and/or psychotic disorder; MDD with psychotic features is excluded;
- 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;
- 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).
- Patients with a diagnosis of DSM-IV-TR Axis II disorder which has a major impact on the patient’s current psychiatric status.
- Patients whose current episode of depression started less than 8 weeks before screening.
- History of hypersensitivity or intolerance to drugs with a similar chemical structure or class to TC-5214.
- 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 184.108.40.206). 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.
- 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.
- Presence of renal insufficiency as evidenced by creatinine clearance of =50 mL/min (measured using Cockroft-Gault equation).
- 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.
- Positive test results for human immunodeficiency virus (HIV) antibody.
- 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.
- Patients on thyroid medication unless at a stable dose for =3 months; thyroid level must be within normal range.
- A diagnosis of cancer (except basal or squamous cell skin carcinoma), unless in remission for at least 5 years.
- Any other severe progressive or uncontrolled medical condition, or chronic medical illness (eg. fibromyalgia, chronic pain conditions, obstructive sleep apnea).
- Known presence of raised intraocular pressure or history of narrow-angle glaucoma.
- Evidence of uncontrolled diabetes mellitus as judged by the investigator or exhibited by hemoglobin A1c (HbA1c) >8%.
- 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).
- History of severe medication allergy/hypersensitivity or ongoing medication allergy/hypersensitivity other than seasonal allergies, as judged by the investigator.
- History of stroke or transient ischemic attack.
- Myocardial infarction within 180 days before screening (Visit 1).
- History of seizures or seizure disorder (single infant febrile seizure with full recovery is acceptable).
- History of head trauma, including closed head injury, in which loss of consciousness occurred.
- Receipt of electroconvulsive therapy (ECT) within the last 2 years.
- Use of prohibited treatments (refer to Table 4 and Table 5for additional information on prohibited medications).
- 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.
- Pregnancy or lactation.
- Clinically significant deviation from the reference range in clinical laboratory test results at enrollment, as judged by the investigator.
- 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).
- History of orthostatic hypotension.
- Clinically significant electrocardiogram (ECG) abnormalities as determined by the investigator and/or central ECG reader.
- 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.
- Involvement in the planning and/or conduct of this study (applies to both Sponsor staff and/or staff at the study site).
- Previous randomization in this study.
- Patients who previously received TC-5214 (S-mecamylamine) or Inversine®.
- 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.
- 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:
- Have had previous allogeneic bone marrow transplant.
- Received non-leukocyte depleted whole blood transfusion in the 120-day period preceding the date of genetic sample collection.
Rush University Medical Center - Treatment Research Center
Psychiatric Medicine Associates
4711 Golf Road #1200
Skokie, IL 60076
Phone: 847 679 8000
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