TC-5214 as add-on the Treatment of Major Depressive Disorder

A Multi-Center, Double Blind, Randomized, Placebo-Controlled, Parallel Group, Flexible Dose Titration, Add-On Study of TC-5214 in the Treatment of MDD With Subjects Who Are Partial Responders or Non-Responders to Citalopram Therapy

This is a multi-center, double blind, randomized, placebo-controlled, parallel group, flexible dose titration study conducted in centers in the USA and India. Following a washout period, subject will be treated with citalopram 20 mg once daily for 4 weeks, then with 40 mg once daily for 4 weeks. Subjects who tolerate 40 mg citalopram, but whose MADRS score is < 50% from baseline, but no lower than 17, will be considered partial or non-responders and will be randomized to receive either placebo or TC-5214 as add-on therapy. TC-5214 or placebo will be started at 2 mg daily (BID dosing), and be titrated based on tolerability and therapeutic response up to 8 mg daily. Approximately 560 subjects will enter the Open Label Phase and approximately 220 will enter the double blind phase of the study.

Study Overview

• Status: Completed
• Conditions: Depression; Major Depressive Disorder
• Intervention / Treatment: Drug: TC-5214 + citalopram; Drug: Placebo + citalopram

Detailed Description

This is a multi-center, double blind, randomized, placebo-controlled, parallel group, flexible dose titration study conducted in centers in the USA and India.

Following a washout period, subject will be treated with citalopram 20 mg once daily for 4 weeks, then with 40 mg once daily for 4 weeks. Subjects who tolerate 40 mg citalopram, but whose MADRS score is reduced 50% from baseline, but no lower than 17, will be considered partial or non-responders and will be randomized to receive either placebo or TC-5214 as Add:-on therapy.

TC-5214 or placebo will be started at 2 mg daily (1mg BID dosing). After 2 weeks treatment, medication can be increased to 4 mg (2mg BID) or continued unchanged. Dose escalation will depend on good tolerability and inadequate therapeutic response. After a further 2 weeks, medication can be increased to 8 mg (4mg BID) if felt appropriate by the investigator. Again, dose escalation will depend on good tolerability and inadequate therapeutic response. At any time during the double blind phase of the study, placebo or TC-5214 can be reduced to the last previous dose level following the emergence of unacceptable adverse event(s).

If a subject is prematurely discontinued from the study between Week 8 and Week 16 for any reason, the investigator will make every effort to perform all evaluations as per protocol, assuming the subject had reached the end of the double blind Add:-on treatment phase. These evaluations are to be made as soon as possible but within 2 weeks of discontinuation.

For the subjects completing the double blind phase of the study, there will be a follow-up visit 2-3 weeks after the last dose of trial medication. At this follow-up, any signs or symptoms of relapse will be evaluated.

• Study Type: Interventional
• Enrollment (Actual): 574
• Phase: Phase 2

Contacts and Locations

Study Locations

• India
  • Andhra Pradesh
    • Guntur, Andhra Pradesh, India, Guntur-522001
      • Sravani Poly Clinic and Mental Health
    • Hyderabaad, Andhra Pradesh, India, 500034
      • Asha hospital
    • Maharanipet, Andhra Pradesh, India, 530002
      • Brain Mind Behaviour Neuroscience Research Institute
    • Vijaywada, Andhra Pradesh, India, 520002
      • VIMHANS
    • Visakhapatnam, Andhra Pradesh, India, 530017
      • Government Hospital for Mental Care, Dept. of Psychiatry
  • Chittoor District, Andhra Pradesh
    • Tirupati, Chittoor District, Andhra Pradesh, India, 517507
      • SV Medical College
  • Dehli
    • New Dehli, Dehli, India, 110029
      • AIIMS
  • Delhi
    • Indraprastha, Delhi, India, 110002
      • GB Pant Hospital
    • New Delhi, Delhi, India, 110065
      • Bhora Nuro Psychiatric Centre
  • Gujarat
    • Ahmedabad, Gujarat, India, 380006
      • Sri Kishna Prasad Psychiatric Nursing Home
  • Karnataka
    • Bangalore, Karnataka, India, 560002
      • Victoria Hospital, Dept. of Psychiatry
    • Bangalore, Karnataka, India, 560034
      • St. John's Hospital
    • Mangalore, Karnataka, India, 572002
      • Adhit Kiran Neuro Psychiatric Centre
    • Mysore, Karnataka, India, 570004
      • JSS Medical College Hospital, Dept. of Psychiatry
  • Madhya Pradesh
    • Bhopal, Madhya Pradesh, India, 462038
      • Bhopal Memorial Hospital & Research Centre, Dept. of Psychiatry
  • Maharashtra
    • Mumbai, Maharashtra, India, 400050
      • Holy Family Hospital
    • Pune, Maharashtra, India, 411004
      • Sanjeevan Hospital
    • Pune, Maharashtra, India, 411030
      • Poona Hospital & Research Centre
    • Pune, Maharashtra, India, 411 004
      • Deenanath Maneshkas Hospital
  • Rajasthan
    • Jaipur, Rajasthan, India, 302006
      • Gautam Hospital & Research Center
  • Tamilnadu
    • Chennai, Tamilnadu, India, 600003
      • Madras Medical College
    • Madurai, Tamilnadu, India, 625 020
      • M.S. Chellamuthu Trust & Research Foundation
  • Uttar Pradesh
    • Kanpur, Uttar Pradesh, India, 208005
      • Mahendru Psychiatric Centre
    • Lucknow, Uttar Pradesh, India, 226003
      • C.S.M. Medical University, Department of Psychiatry
• United States
  • Florida
    • Miami, Florida, United States, 33143
      • Aurora Clinical Trials
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Community Research
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of major depressive disorder (MDD) according to DSM-IV and confirmed via MINI diagnostic scale
2. No more than 1 prior antidepressant course of treatment before trial entry.
3. Able to give written informed consent.
4. MADRS score greater than 27.
5. CGI-S score greater than or equal to 4.
6. No clinically significant abnormality on physical examination, vital signs, ECG or laboratory tests at screening.
7. Women of child bearing potential must: a) have a negative urine pregnancy test, b) not be nursing, and c) be willing to use acceptable methods of contraception throughout the study period.

Exclusion Criteria:

1. Any co morbid psychiatric illness confirmed by MINI diagnostic scale, especially bipolar disorder, schizophrenia, dementia, or PTSD
2. Subjects with significant suicidal risk upon clinical assessment utilizing the M.I.N.I.
3. History of alcohol or drug abuse over the last 6 months
4. History of seizures or seizure disorders
5. Any other severe progressive and uncontrolled medical condition
6. For other controlled medical conditions, medication to be unchanged over the 2 months preceding screening, or else the subject will be excluded
7. Subjects with Glaucoma, Kidney Disease or Heart Disease
8. Known hypersensitivity to mecamylamine
9. Other investigational drug in previous 30 days
10. Screening QTcB or QTcF > 450 msec
11. Current or prior citalopram treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: citalopram + TC-5214	Drug: TC-5214 + citalopram; TC-5214 (as TC-5214-23) will be provided as white, opaque, hard-gelatin capsules in strengths of 1, 2, and 4 mg.; Other Names: Mecamylamine
Placebo Comparator: citalopram + placebo	Drug: Placebo + citalopram; Placebo will be provided with exactly the same shape, size and appearance. Subjects will take 2, 4, or 8 mg of study drug (or matching placebo), divided BID.; Other Names: Placebo; Citalopram

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mean change between TC-5214 and placebo from DB baseline (Week 8) of the HAMD-17 score, at Week 16.	16 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events	Treatment emergent adverse events (TEAEs) will be tabulated and summarized by presenting the incidence (number of subjects) in each treatment group.	16 Weeks

Collaborators and Investigators

• Sponsor: Targacept Inc.
• Investigators: Principal Investigator: Alfredo N Rivera, MD, Community Research

Publications and helpful links

General Publications

• Xu H, Henningsson A, Alverlind S, Tummala R, Toler S, Beaver JS, Al-Huniti N. Population pharmacokinetics of TC-5214, a nicotinic channel modulator, in phase I and II clinical studies. J Clin Pharmacol. 2014 Jun;54(6):707-18. doi: 10.1002/jcph.264. Epub 2014 Jan 16.
• Khan SA, Revicki DA, Hassan M, Locklear JC, Friedman LA, Mannix S, Tummala R, Dunbar GC, Eriksson H, Sheehan DV. Assessing the Reliability and Validity of the Sheehan Irritability Scale in Patients With Major Depressive Disorder. J Clin Psychiatry. 2016 Aug;77(8):1080-6. doi: 10.4088/JCP.14m09719.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): May 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: June 4, 2008
• First Submitted That Met QC Criteria: June 4, 2008
• First Posted (Estimate): June 6, 2008

Study Record Updates

• Last Update Posted (Estimate): June 21, 2013
• Last Update Submitted That Met QC Criteria: June 13, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: depression
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antiparkinson Agents; Anti-Dyskinesia Agents; Ganglionic Blockers; Nicotinic Antagonists; Citalopram; Dexetimide; Mecamylamine
• Other Study ID Numbers: TC-5214-23-CRD-001