A Study to Assess the Efficacy and Safety of TC-5214 as an Adjunct Therapy in Patients With Major Depressive Disorder
Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT01153347
Collaborator
Targacept Inc. (Industry)
2,409
99
4
19
24.3
1.3
Study Details
Study Description
Brief Summary
The purpose of this study is to determine if TC-5214 or placebo (a tablet that looks like medicine tablet or capsule, but contains no active medicine) is safe and effective when taken together with another antidepressant.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
2409 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official 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
Study Start Date
:
Jun 1, 2010
Actual Primary Completion Date
:
Jan 1, 2012
Actual Study Completion Date
:
Jan 1, 2012
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: SSRI/Serotonin/SNRI+ TC-5214 0.5 mg Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID |
Drug: TC-5214
Tablet, oral, twice daily for 8 weeks
|
| Experimental: SSRI/Serotonin/SNRI + TC-5214 2 mg Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID |
Drug: TC-5214
Tablet, oral, twice daily for 8 weeks
|
| Experimental: SSRI/Serotonin/SNRI + TC-5214 4 mg Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID |
Drug: TC-5214
Tablet, oral, twice daily for 8 weeks
|
| Placebo Comparator: SSRI/Serotonin/SNRI + Placebo Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
Drug: Placebo
Tablet, oral, twice daily for 8 weeks
|
Outcome Measures
Primary Outcome Measures
- Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment. [Randomization (Week 8) to end of treatment (Week 16)]
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
Secondary Outcome Measures
- Response in Depressive Symptoms of Major Depressive Disorder (MDD), Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score at End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]
The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score at end of treatment (Week 16) was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
- Remission in Depressive Symptoms of MDD, Defined as MADRS Total Score of ≤8 at End of Treatment (Week 16) [Week 16]
The percentage of patients with a MADRS total score of ≤8 at end of treatment (Week 16) was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
- Early and Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 10, Week 12, Week 14, and End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16); Week 10, Week 12, Week 14, and Week 16]
The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 10, Week 12, Week 14, and end of treatment (Week 16) was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
- Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 12, Week 14, and End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16); Week 12, Week 14, and Week 16]
The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 12, Week 14, and end of treatment (Week 16) was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
- Sustained Remission, Defined as a MADRS Total Score of ≤8 at Week 12, Week 14, and End of Treatment (Week 16) [Week 12, Week 14, Week 16]
The percentage of patients with a MADRS total score of ≤8 at Week 12, Week 14, and end of treatment (Week 16)was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
- Change in Depressive Symptoms From Randomization (Week 8) to End of Treatment (Week 16) as Measured by Hamilton Rating Scale for Depression-17 Items (HAMD-17) Total Score [Randomization (Week 8) to end of treatment (Week 16)]
A 17-item, clinician-rated scale that assesses depressive symptoms. The HAMD-17 consists of 17 symptoms, each of which is rated from 0 to 2 or 0 to 4, where 0 is none/absent. The HAMD-17 total score is calculated as the sum of the 17 individual symptom scores; the total score can range from 0 to 52. Higher HAMD-17 scores indicate more severe depression.
- Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 8) to End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]
A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. Higher CGI-S scores indicate greater illness severity.
- Response in the Clinical Global Impression-Improvement (CGI-I) Defined as CGI-I Rating of "Very Much Improved" or "Much Improved" From Randomization (Week 8) to End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]
A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. CGI-I scores >4 indicate worsening, while scores <4 indicate improvement.
- Change in Hamilton Anxiety Scale (HAM-A) Total Score From Randomization (Week 8) to End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]
A 14-item clinician-administered scale for the evaluation of anxiety symptoms. Each HAM-A item is rated on a 0 to 4 scale, the total score can range from 0 to 56. Higher HAM-A scores indicate higher levels of anxiety.
- Change in MADRS Total Score From Randomization (Week 8) to Week 9 [Randomization (Week 8) to Week 9]
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
- Change in MADRS Total Score From Randomization (Week 8) to Week 10 [Randomization (Week 8) to Week 10]
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
- Change in MADRS Total Score From Randomization (Week 8) to Week 12 [Randomization (Week 8) to Week 12]
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
- Change in MADRS Total Score From Randomization (Week 8) to Week 14 [Randomization (Week 8) to Week 14]
A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms.
- Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by the Sheehan Disability Scale (SDS) Total Score [Randomization (Week 8) to end of treatment (Week 16)]
Sheehan Disability Scale (SDS) is 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The SDS total score is calculated as the sum of the score for the 3 inter-correlated domains (school/work, social life, and family life/home responsibilities) and ranges from 0 (unimpaired) to 30 (highly impaired).
- Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Work/School Domain Score [Randomization (Week 8) to end of treatment (Week 16)]
A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the work/school domain score is 0- 10, where 10 is considered to be 'highly impaired'.
- Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Social Life Domain Score [Randomization (Week 8) to end of treatment (Week 16)]
A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS social life domain score is 0- 10, where 10 is considered to be 'highly impaired'.
- Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Family Life/Home Responsibilities Domain Score [Randomization (Week 8) to end of treatment (Week 16)]
A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS family life/home responsibilities domain score is 0- 10, where 10 is considered to be 'highly impaired'.
- Change in Overall Quality of Life and Satisfaction From Randomization (Week 8) to End of Treatment (Week 16) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score [Randomization (Week 8) to end of treatment (Week 16)]
The Q-LES-Q-SF total score is derived by summing item scores 1 to 14. Higher scores are indicative of greater enjoyment or satisfaction in each domain. The Q-LES-Q-SF % maximum total score is calculated as 100% × (Q-LES-Q-SF total score - 14) / 56, and can range from 0% to 100%.
- Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form(Q LES-Q-SF)Item 15 [Randomization (Week 8) to end of treatment (Week 16)]
The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 15th item queries respondents' satisfaction with the medication they are taking, rated on a 1 to 4 scale, score 0 indicates that no medication was taken. Higher scores are indicative of greater satisfaction.
- Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 16 [Randomization (Week 8) to end of treatment (Week 16)]
The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 16th item is a global rating of overall life satisfaction and contentment, rated on a 1 to 5 scale. Higher scores are indicative of greater satisfaction.
- Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]
A self-assessment questionnaire that provides 2 measures of health status. The EQ-5D index score is a weighted linear combination over 5 dimensions of health status. The score for each of the 5 dimensions can range from 1 to 3, and an equation is used to calculate the EQ-5D index score. The EQ-5D index score can range from possible negative values (minimum -0.415) to a maximum of 1.0. The EQ-VAS is a visual analog scale with a range of 0 to 100. For both variables, a higher score indicates a better health state.
- Change in Irritability Symptoms as Measured by the Sheehan Irritability Scale (SIS) Total Score From Randomization (Week 8) to End of Treatment (Week 16) [Randomization (Week 8) to end of treatment (Week 16)]
A self-administered scale to be used by clinical subjects to rate suffering over the past week with regard to irritability symptoms. The total SIS score is the sum of 7 items, and ranges from 0 to 70. Each item is assessed on an 11- point scale where 0=not at all, 1-3=mildly, 4-6=moderately, 7-9=markedly, and 10=extremely. The SIS also records the number of days impaired by irritability.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 65 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Provision of signed and dated informed consent before initiation of any study-related procedures.
-
The patient must have a clinical diagnosis of major depressive disorder (MDD) with inadequate response to no more than one antidepressant.
-
Outpatient status at enrollment and randomization.
Exclusion Criteria:
-
Patients with a lifetime history of bipolar disorder, psychotic disorder or post-traumatic stress disorder.
-
Patients 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.
-
History of renal insufficiency or impairment or conditions that could affect absorption or metabolism of investigational product.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Birmingham | Alabama | United States | |
| 2 | Research Site | Tucson | Arizona | United States | |
| 3 | Research Site | Conway | Arkansas | United States | |
| 4 | Research Site | Little Rock | Arkansas | United States | |
| 5 | Research Site | Arcadia | California | United States | |
| 6 | Research Site | Beverly Hills | California | United States | |
| 7 | Research Site | Garden Grove | California | United States | |
| 8 | Research Site | Los Angeles | California | United States | |
| 9 | Research Site | Newport Beach | California | United States | |
| 10 | Research Site | Oakland | California | United States | |
| 11 | Research Site | Oceanside | California | United States | |
| 12 | Research Site | Pico Rivera | California | United States | |
| 13 | Research Site | Santa Ana | California | United States | |
| 14 | Research Site | Upland | California | United States | |
| 15 | Research Site | Denver | Colorado | United States | |
| 16 | Research Site | Cromwell | Connecticut | United States | |
| 17 | Research Site | New London | Connecticut | United States | |
| 18 | Research Site | Norwich | Connecticut | United States | |
| 19 | Research Site | Washington | District of Columbia | United States | |
| 20 | Research Site | Bradenton | Florida | United States | |
| 21 | Research Site | Ft Myers | Florida | United States | |
| 22 | Research Site | Ft Walton Beach | Florida | United States | |
| 23 | Research Site | Gainsville | Florida | United States | |
| 24 | Research Site | Jacksonville | Florida | United States | |
| 25 | Research Site | North Miami | Florida | United States | |
| 26 | Research Site | Orlando | Florida | United States | |
| 27 | Research Site | Plantation | Florida | United States | |
| 28 | Research Site | South Miami | Florida | United States | |
| 29 | Research Site | St Petersburg | Florida | United States | |
| 30 | Research Site | Tampa | Florida | United States | |
| 31 | Research Site | West Palm Beach | Florida | United States | |
| 32 | Research Site | Atlanta | Georgia | United States | |
| 33 | Research Site | Roswell | Georgia | United States | |
| 34 | Research Site | Hoffman Estates | Illinois | United States | |
| 35 | Research Site | Joliet | Illinois | United States | |
| 36 | Research Site | Schaumburg | Illinois | United States | |
| 37 | Research Site | Skokie | Illinois | United States | |
| 38 | Research Site | Valparaiso | Indiana | United States | |
| 39 | Research Site | Prairie Village | Kansas | United States | |
| 40 | Research Site | Wichita | Kansas | United States | |
| 41 | Research Site | Florence | Kentucky | United States | |
| 42 | Research Site | Baltimore | Maryland | United States | |
| 43 | Research Site | Gaithersburg | Maryland | United States | |
| 44 | Research Site | Boston | Massachusetts | United States | |
| 45 | Research Site | Weymouth | Massachusetts | United States | |
| 46 | Research Site | Flowood | Mississippi | United States | |
| 47 | Research Site | St. Louis | Missouri | United States | |
| 48 | Research Site | North Platte | Nebraska | United States | |
| 49 | Research Site | Toms River | New Jersey | United States | |
| 50 | Research Site | Willingboro | New Jersey | United States | |
| 51 | Research Site | Mount Kisco | New York | United States | |
| 52 | Research Site | New York | New York | United States | |
| 53 | Research Site | Rochester | New York | United States | |
| 54 | Research Site | Staten Island | New York | United States | |
| 55 | Research Site | Avon Lake | Ohio | United States | |
| 56 | Research Site | Beachwood | Ohio | United States | |
| 57 | Research Site | Beechwood | Ohio | United States | |
| 58 | Research Site | Cincinnati | Ohio | United States | |
| 59 | Research Site | Mason | Ohio | United States | |
| 60 | Research Site | Oklahoma City | Oklahoma | United States | |
| 61 | Research Site | Portland | Oregon | United States | |
| 62 | Research Site | Allentown | Pennsylvania | United States | |
| 63 | Research Site | Norristown | Pennsylvania | United States | |
| 64 | Research Site | Pittsburgh | Pennsylvania | United States | |
| 65 | Research Site | Sellersvillle | Pennsylvania | United States | |
| 66 | Research Site | Lincoln | Rhode Island | United States | |
| 67 | Research Site | Charleston | South Carolina | United States | |
| 68 | Research Site | Memphis | Tennessee | United States | |
| 69 | Research Site | Austin | Texas | United States | |
| 70 | Research Site | Dallas | Texas | United States | |
| 71 | Research Site | Irving | Texas | United States | |
| 72 | Research Site | San Antonio | Texas | United States | |
| 73 | Research Site | Sugar Land | Texas | United States | |
| 74 | Research Site | Murray | Utah | United States | |
| 75 | Research Site | Bellevue | Washington | United States | |
| 76 | Research Site | Bothell | Washington | United States | |
| 77 | Research Site | Seattle | Washington | United States | |
| 78 | Research Site | South Kirkland | Washington | United States | |
| 79 | Research Site | Spokane | Washington | United States | |
| 80 | Research Site | Guntur | Andhra Pradesh | India | |
| 81 | Research Site | Vijayawada | Andhra Pradesh | India | |
| 82 | Research Site | Vishakhapatnam | Andhra Pradesh | India | |
| 83 | Research Site | Anand | Gujarat | India | |
| 84 | Research Site | Junagadh | Gujarat | India | |
| 85 | Research Site | Vadodara | Gujarat | India | |
| 86 | Research Site | Rajkot | Gujrat | India | |
| 87 | Research Site | Bangalore | Karnataka | India | |
| 88 | Research Site | Aurangabad | Maharashtra | India | |
| 89 | Research Site | Pune | Maharashtra | India | |
| 90 | Research Site | Nashik | Mahara | India | |
| 91 | Research Site | Durham | NC | India | |
| 92 | Research Site | Chennai | Tamil Nadu | India | |
| 93 | Research Site | Madurai | Tamilnadu | India | |
| 94 | Research Site | Lucknow | Uttar Pradesh | India | |
| 95 | Research Site | Varanasi | Uttar Prad | India | |
| 96 | Research Site | Kanpur | India | ||
| 97 | Research Site | Karnataka | India | ||
| 98 | Research Site | Mysore | India | ||
| 99 | Research Site | San Juan | Puerto Rico |
Sponsors and Collaborators
- AstraZeneca
- Targacept Inc.
Investigators
- Study Director: Hans A. Eriksson, MD,PhD, MBA, AstraZeneca
- Principal Investigator: Andrew J. Cutler, MD, Florida Clinical Research Center, LLC
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01153347
Other Study ID Numbers:
- D4130C00004
First Posted:
Jun 30, 2010
Last Update Posted:
Apr 11, 2014
Last Verified:
Mar 1, 2014
Keywords provided by AstraZeneca
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | This multicenter study was conducted in the US and India between 15 June 2010 and 31 January 2012. |
|---|---|
| Pre-assignment Detail | The study had an up to 21-day screening/washout period, and an 8-week prospective open-label antidepressant treatment (ADT) period to identify the target patient population of inadequate responders to ADT (<50% reduction in HAMD-17 total score during the prospective open-label ADT period, a HAMD-17 total score of ≥16 and a CGI-S score ≥4). |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Period Title: Overall Study | ||||
| STARTED | 160 | 160 | 160 | 161 |
| Received Treatment | 160 | 158 | 158 | 160 |
| COMPLETED | 127 | 116 | 110 | 129 |
| NOT COMPLETED | 33 | 44 | 50 | 32 |
Baseline Characteristics
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID | Total of all reporting groups |
| Overall Participants | 160 | 160 | 160 | 161 | 641 |
| Age (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
40.6
(11.78)
|
42.1
(11.77)
|
42.1
(11.35)
|
43.2
(11.92)
|
42.0
(11.72)
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
85
53.1%
|
91
56.9%
|
93
58.1%
|
96
59.6%
|
365
56.9%
|
| Male |
75
46.9%
|
69
43.1%
|
67
41.9%
|
65
40.4%
|
276
43.1%
|
| Race/Ethnicity, Customized (participants) [Number] | |||||
| White |
87
54.4%
|
100
62.5%
|
91
56.9%
|
103
64%
|
381
59.4%
|
| Black or African American |
20
12.5%
|
23
14.4%
|
27
16.9%
|
14
8.7%
|
84
13.1%
|
| Asian |
50
31.3%
|
35
21.9%
|
40
25%
|
42
26.1%
|
167
26.1%
|
| Native Hawaiian or other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
1
0.6%
|
1
0.2%
|
| American Indian or Alaska Native |
0
0%
|
1
0.6%
|
0
0%
|
0
0%
|
1
0.2%
|
| Other |
3
1.9%
|
1
0.6%
|
2
1.3%
|
1
0.6%
|
7
1.1%
|
| Hamilton Rating Scale for Depression-17 items (HAMD-17) total score at randomization (Scores on a scale) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [Scores on a scale] |
22.3
(3.98)
|
21.5
(3.74)
|
22.0
(4.07)
|
22.1
(4.08)
|
22.0
(3.97)
|
| Montgomery-Asberg Depression Rating Scale (MADRS) total score at randomization (Scores on a scale) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [Scores on a scale] |
26.86
(6.331)
|
26.37
(6.036)
|
27.06
(5.854)
|
26.70
(6.809)
|
26.75
(6.261)
|
Outcome Measures
| Title | Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score From Randomization to End of Treatment. |
|---|---|
| Description | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 155 | 156 | 152 | 157 |
| Least Squares Mean (Standard Error) [units on a scale] |
-12.1
(0.81)
|
-11.8
(0.83)
|
-11.3
(0.84)
|
-11.2
(0.80)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Mixed model repeated measures (MMRM) includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.000 |
| Comments | The adjusted p-value protects the overall family-wise error rate by taking into account the multiple comparisons between the TC-5214 doses for both the primary efficacy variable (MADRS) and the key secondary efficacy variable (SDS). | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.9 | |
| Confidence Interval |
(2-Sided) 95% -2.96 to 1.24 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.07 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Mixed model repeated measures (MMRM) includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.000 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.6 | |
| Confidence Interval |
(2-Sided) 95% -2.67 to 1.57 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.08 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Mixed model repeated measures (MMRM) includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.000 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.1 | |
| Confidence Interval |
(2-Sided) 95% -2.26 to 2.04 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.09 |
|
| Estimation Comments | ||
| Title | Response in Depressive Symptoms of Major Depressive Disorder (MDD), Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score at End of Treatment (Week 16) |
|---|---|
| Description | The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score at end of treatment (Week 16) was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 155 | 156 | 152 | 157 |
| Number [percentage of participants analyzed] |
43.9
27.4%
|
39.7
24.8%
|
38.8
24.3%
|
42.7
26.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.967 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.01 | |
| Confidence Interval |
(2-Sided) 95% 0.64 to 1.60 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.24 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.670 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.90 | |
| Confidence Interval |
(2-Sided) 95% 0.57 to 1.43 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.21 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.544 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.87 | |
| Confidence Interval |
(2-Sided) 95% 0.54 to 1.38 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.21 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
| Title | Remission in Depressive Symptoms of MDD, Defined as MADRS Total Score of ≤8 at End of Treatment (Week 16) |
|---|---|
| Description | The percentage of patients with a MADRS total score of ≤8 at end of treatment (Week 16) was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 155 | 156 | 152 | 157 |
| Number [percentage of participants analyzed] |
29.0
18.1%
|
26.9
16.8%
|
23.7
14.8%
|
29.9
18.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.730 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.91 | |
| Confidence Interval |
(2-Sided) 95% 0.55 to 1.53 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.24 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.671 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.89 | |
| Confidence Interval |
(2-Sided) 95% 0.53 to 1.50 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.23 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.308 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.76 | |
| Confidence Interval |
(2-Sided) 95% 0.45 to 1.29 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.20 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
| Title | Early and Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 10, Week 12, Week 14, and End of Treatment (Week 16) |
|---|---|
| Description | The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 10, Week 12, Week 14, and end of treatment (Week 16) was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16); Week 10, Week 12, Week 14, and Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 148 | 153 | 145 | 153 |
| Number [percentage of participants analyzed] |
8.8
5.5%
|
7.8
4.9%
|
8.3
5.2%
|
8.5
5.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.905 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.95 | |
| Confidence Interval |
(2-Sided) 95% 0.42 to 2.15 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.40 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.864 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.93 | |
| Confidence Interval |
(2-Sided) 95% 0.41 to 2.14 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.39 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.958 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.98 | |
| Confidence Interval |
(2-Sided) 95% 0.43 to 2.25 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.42 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
| Title | Sustained Response, Defined as a ≥50% Reduction From Randomization (Week 8) in MADRS Total Score and a MADRS Total Score of ≤12 at Week 12, Week 14, and End of Treatment (Week 16) |
|---|---|
| Description | The percentage of patients with a ≥50% reduction from randomization (Week 8) in MADRS total score and a MADRS total score of ≤12 at Week 12, Week 14, and end of treatment (Week 16) was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16); Week 12, Week 14, and Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 145 | 150 | 143 | 151 |
| Number [percentage of patients analyzed] |
15.9
|
18.7
|
14.0
|
15.9
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.778 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.91 | |
| Confidence Interval |
(2-Sided) 95% 0.48 to 1.73 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.30 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.532 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.22 | |
| Confidence Interval |
(2-Sided) 95% 0.66 to 2.24 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.38 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.633 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.85 | |
| Confidence Interval |
(2-Sided) 95% 0.44 to 1.64 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.29 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
| Title | Sustained Remission, Defined as a MADRS Total Score of ≤8 at Week 12, Week 14, and End of Treatment (Week 16) |
|---|---|
| Description | The percentage of patients with a MADRS total score of ≤8 at Week 12, Week 14, and end of treatment (Week 16)was calculated. A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Week 12, Week 14, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 146 | 150 | 144 | 152 |
| Number [percentage of participants analyzed] |
10.3
6.4%
|
12.7
7.9%
|
7.6
4.8%
|
9.2
5.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.949 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.03 | |
| Confidence Interval |
(2-Sided) 95% 0.46 to 2.31 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.42 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.253 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.57 | |
| Confidence Interval |
(2-Sided) 95% 0.72 to 3.40 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.62 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization MADRS total score as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.763 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.88 | |
| Confidence Interval |
(2-Sided) 95% 0.37 to 2.08 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.39 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
| Title | Change in Depressive Symptoms From Randomization (Week 8) to End of Treatment (Week 16) as Measured by Hamilton Rating Scale for Depression-17 Items (HAMD-17) Total Score |
|---|---|
| Description | A 17-item, clinician-rated scale that assesses depressive symptoms. The HAMD-17 consists of 17 symptoms, each of which is rated from 0 to 2 or 0 to 4, where 0 is none/absent. The HAMD-17 total score is calculated as the sum of the 17 individual symptom scores; the total score can range from 0 to 52. Higher HAMD-17 scores indicate more severe depression. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 147 | 144 | 142 | 150 |
| Least Squares Mean (Standard Error) [units on a scale] |
-10.1
(0.79)
|
-9.7
(0.79)
|
-9.5
(0.79)
|
-9.1
(0.78)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Analysis of covariance (ANCOVA) with randomization HAMD-17 total score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.207 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -1.0 | |
| Confidence Interval |
(2-Sided) 95% -2.51 to 0.55 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.78 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Analysis of covariance (ANCOVA) with randomization HAMD-17 total score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.427 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.6 | |
| Confidence Interval |
(2-Sided) 95% -2.16 to 0.91 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.78 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Analysis of covariance (ANCOVA) with randomization HAMD-17 total score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.591 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.4 | |
| Confidence Interval |
(2-Sided) 95% -1.96 to 1.12 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.78 |
|
| Estimation Comments | ||
| Title | Change in the Clinician-rated Global Outcome of Severity as Measured by the Clinical Global Impression-Severity (CGI-S) Score From Randomization (Week 8) to End of Treatment (Week 16) |
|---|---|
| Description | A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. Higher CGI-S scores indicate greater illness severity. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 155 | 156 | 152 | 157 |
| Least Squares Mean (Standard Error) [units on a scale] |
-1.3
(0.10)
|
-1.3
(0.11)
|
-1.2
(0.11)
|
-1.2
(0.10)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization CGI-S total score as a covariate. Treatment, visit, and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.551 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.1 | |
| Confidence Interval |
() 95% -0.34 to 0.18 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.13 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization CGI-S total score as a covariate. Treatment, visit, and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.487 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.1 | |
| Confidence Interval |
(2-Sided) 95% -0.36 to 0.17 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.13 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization CGI-S total score as a covariate. Treatment, visit, and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.780 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -0.23 to 0.31 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.14 |
|
| Estimation Comments | ||
| Title | Response in the Clinical Global Impression-Improvement (CGI-I) Defined as CGI-I Rating of "Very Much Improved" or "Much Improved" From Randomization (Week 8) to End of Treatment (Week 16) |
|---|---|
| Description | A 3-part, clinician-administered scale that rates the improvement or worsening of the patient's illness from randomization (baseline). Each item is scored on a 1 to 7 scale. CGI-I scores >4 indicate worsening, while scores <4 indicate improvement. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 155 | 156 | 152 | 157 |
| Number [percentage of participants analyzed] |
48.4
30.3%
|
49.4
30.9%
|
37.5
23.4%
|
47.8
29.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization Clinical Global Impression Severity (CGI-S) as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.908 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.97 | |
| Confidence Interval |
(2-Sided) 95% 0.62 to 1.53 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.23 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization Clinical Global Impression Severity (CGI-S) as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.803 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.06 | |
| Confidence Interval |
(2-Sided) 95% 0.67 to 1.67 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.24 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | Logistic regression model including treatment and pooled center as fixed effects and the randomization Clinical Global Impression Severity (CGI-S) as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.066 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.65 | |
| Confidence Interval |
(2-Sided) 95% 0.41 to 1.03 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.15 |
|
| Estimation Comments | TC-5214 is the numerator in the OR, OR>1 represents a result in favor of TC-5214. | |
| Title | Change in Hamilton Anxiety Scale (HAM-A) Total Score From Randomization (Week 8) to End of Treatment (Week 16) |
|---|---|
| Description | A 14-item clinician-administered scale for the evaluation of anxiety symptoms. Each HAM-A item is rated on a 0 to 4 scale, the total score can range from 0 to 56. Higher HAM-A scores indicate higher levels of anxiety. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 147 | 144 | 142 | 150 |
| Least Squares Mean (Standard Error) [units on a scale] |
-7.07
(0.648)
|
-6.46
(0.652)
|
-6.75
(0.655)
|
-6.24
(0.641)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | An analysis of covariance (ANCOVA) with randomization HAM-A total score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.202 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.82 | |
| Confidence Interval |
(2-Sided) 95% -2.091 to 0.442 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.645 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | An analysis of covariance (ANCOVA) with randomization HAM-A total score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.738 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.22 | |
| Confidence Interval |
(2-Sided) 95% -1.487 to 1.055 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.647 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | An analysis of covariance (ANCOVA) with randomization HAM-A total score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.433 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.51 | |
| Confidence Interval |
(2-Sided) 95% -1.787 to 0.767 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.650 |
|
| Estimation Comments | ||
| Title | Change in MADRS Total Score From Randomization (Week 8) to Week 9 |
|---|---|
| Description | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Randomization (Week 8) to Week 9 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 152 | 150 | 146 | 152 |
| Least Squares Mean (Standard Error) [units on a scale] |
-4.0
(0.52)
|
-5.1
(0.52)
|
-4.0
(0.52)
|
-5.0
(0.52)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.097 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 1.0 | |
| Confidence Interval |
(2-Sided) 95% -0.18 to 2.22 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.61 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.882 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.1 | |
| Confidence Interval |
(2-Sided) 95% -1.29 to 1.11 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.61 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.100 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 1.0 | |
| Confidence Interval |
(2-Sided) 95% -0.19 to 2.23 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.62 |
|
| Estimation Comments | ||
| Title | Change in MADRS Total Score From Randomization (Week 8) to Week 10 |
|---|---|
| Description | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Randomization (Week 8) to Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 150 | 146 | 139 | 148 |
| Least Squares Mean (Standard Error) [units on a scale] |
-6.3
(0.60)
|
-6.9
(0.60)
|
-7.3
(0.61)
|
-7.1
(0.60)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.303 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.8 | |
| Confidence Interval |
(2-Sided) 95% -0.69 to 2.22 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.74 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.793 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.2 | |
| Confidence Interval |
(2-Sided) 95% -1.26 to 1.65 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.74 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.762 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.2 | |
| Confidence Interval |
(2-Sided) 95% -1.70 to 1.25 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.75 |
|
| Estimation Comments | ||
| Title | Change in MADRS Total Score From Randomization (Week 8) to Week 12 |
|---|---|
| Description | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Randomization (Week 8) to Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 142 | 135 | 128 | 145 |
| Least Squares Mean (Standard Error) [units on a scale] |
-9.4
(0.70)
|
-9.4
(0.71)
|
-8.9
(0.73)
|
-8.5
(0.70)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.339 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.9 | |
| Confidence Interval |
(2-Sided) 95% -2.65 to 0.92 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.91 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.321 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.9 | |
| Confidence Interval |
(2-Sided) 95% -2.70 to 0.89 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.91 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.680 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.4 | |
| Confidence Interval |
(2-Sided) 95% -2.20 to 1.43 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.92 |
|
| Estimation Comments | ||
| Title | Change in MADRS Total Score From Randomization (Week 8) to Week 14 |
|---|---|
| Description | A 10-item scale for the evaluation of depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. The MADRS total score is calculated as the sum of the 10 individual item scores; the total score can range from 0 to 60. Higher MADRS scores indicate higher levels of depressive symptoms. |
| Time Frame | Randomization (Week 8) to Week 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 140 | 127 | 119 | 134 |
| Least Squares Mean (Standard Error) [units on a scale] |
-11.0
(0.74)
|
-11.3
(0.76)
|
-10.6
(0.77)
|
-10.7
(0.74)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.737 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.3 | |
| Confidence Interval |
(2-Sided) 95% -2.23 to 1.58 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.97 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.547 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.6 | |
| Confidence Interval |
(2-Sided) 95% -2.52 to 1.33 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.98 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization MADRS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.953 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.1 | |
| Confidence Interval |
(2-Sided) 95% -1.89 to 2.01 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.99 |
|
| Estimation Comments | ||
| Title | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by the Sheehan Disability Scale (SDS) Total Score |
|---|---|
| Description | Sheehan Disability Scale (SDS) is 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The SDS total score is calculated as the sum of the score for the 3 inter-correlated domains (school/work, social life, and family life/home responsibilities) and ranges from 0 (unimpaired) to 30 (highly impaired). |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 152 | 148 | 149 | 153 |
| Least Squares Mean (Standard Error) [units on a scale] |
-5.53
(0.631)
|
-5.45
(0.643)
|
-4.53
(0.651)
|
-4.93
(0.627)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization SDS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.000 |
| Comments | The adjusted p-value protects the overall family-wise error rate by taking into account the multiple comparisons between the TC-5214 doses for both the primary efficacy variable (MADRS) and the key secondary efficacy variable (SDS). | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.60 | |
| Confidence Interval |
(2-Sided) 95% -2.069 to 0.864 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.746 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization SDS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.000 |
| Comments | The adjusted p-value protects the overall family-wise error rate by taking into account the multiple comparisons between the TC-5214 doses for both the primary efficacy variable (MADRS) and the key secondary efficacy variable (SDS). | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.52 | |
| Confidence Interval |
(2-Sided) 95% -2.004 to 0.960 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.755 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization SDS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.000 |
| Comments | The adjusted p-value protects the overall family-wise error rate by taking into account the multiple comparisons between the TC-5214 doses for both the primary efficacy variable (MADRS) and the key secondary efficacy variable (SDS). | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.40 | |
| Confidence Interval |
(2-Sided) 95% -1.095 to 1.896 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.761 |
|
| Estimation Comments | ||
| Title | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Work/School Domain Score |
|---|---|
| Description | A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the work/school domain score is 0- 10, where 10 is considered to be 'highly impaired'. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 132 | 123 | 134 | 137 |
| Least Squares Mean (Standard Error) [units on a scale] |
-1.7
(0.21)
|
-1.8
(0.22)
|
-1.7
(0.21)
|
-1.7
(0.21)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS work/school domain score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.953 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -0.56 to 0.59 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.29 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS work/school domain score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.868 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -0.64 to 0.54 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.30 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS work/school domain score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.792 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.1 | |
| Confidence Interval |
(2-Sided) 95% -0.50 to 0.66 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.30 |
|
| Estimation Comments | ||
| Title | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Social Life Domain Score |
|---|---|
| Description | A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS social life domain score is 0- 10, where 10 is considered to be 'highly impaired'. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 152 | 148 | 149 | 153 |
| Least Squares Mean (Standard Error) [units on a scale] |
-1.9
(0.22)
|
-1.9
(0.23)
|
-1.6
(0.23)
|
-1.9
(0.22)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS social life domain score. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.915 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -0.54 to 0.48 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.26 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS social life domain score. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.972 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -0.51 to 0.53 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.26 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS social life domain score. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.237 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.3 | |
| Confidence Interval |
(2-Sided) 95% -0.21 to 0.84 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.27 |
|
| Estimation Comments | ||
| Title | Change in Functional Impairment From Randomization (Week 8) to End of Treatment (Week 16) as Measured by SDS Family Life/Home Responsibilities Domain Score |
|---|---|
| Description | A 5-item, self-administered scale that measures the extent a patient is impaired by their disease. Higher scores indicate more severe impairment. The 3 inter-correlated domains are school/work, social life, and family life/home responsibilities. The numerical rating for the SDS family life/home responsibilities domain score is 0- 10, where 10 is considered to be 'highly impaired'. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 152 | 148 | 149 | 153 |
| Least Squares Mean (Standard Error) [units on a scale] |
-1.9
(0.22)
|
-1.8
(0.23)
|
-1.6
(0.23)
|
-1.6
(0.22)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS family life/home responsibilities domain score. Treatment, visit and treatment by visit interaction are effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.213 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.3 | |
| Confidence Interval |
(2-Sided) 95% -0.87 to 0.19 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.27 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS family life/home responsibilities domain score. Treatment, visit and treatment by visit interaction are effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.343 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.3 | |
| Confidence Interval |
(2-Sided) 95% -0.80 to 0.28 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.27 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization SDS family life/home responsibilities domain score. Treatment, visit and treatment by visit interaction are effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.971 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -0.55 to 0.53 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.28 |
|
| Estimation Comments | ||
| Title | Change in Overall Quality of Life and Satisfaction From Randomization (Week 8) to End of Treatment (Week 16) by Assessing the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) % Maximum Total Score |
|---|---|
| Description | The Q-LES-Q-SF total score is derived by summing item scores 1 to 14. Higher scores are indicative of greater enjoyment or satisfaction in each domain. The Q-LES-Q-SF % maximum total score is calculated as 100% × (Q-LES-Q-SF total score - 14) / 56, and can range from 0% to 100%. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 152 | 148 | 144 | 151 |
| Least Squares Mean (Standard Error) [units on a scale] |
12.81
(1.470)
|
11.42
(1.483)
|
8.83
(1.499)
|
10.71
(1.467)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | ANCOVA with randomization Q-LES-Q-SF % maximum total score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.215 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 2.10 | |
| Confidence Interval |
(2-Sided) 95% -1.224 to 5.431 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.694 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | ANCOVA with randomization Q-LES-Q-SF % maximum total score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.673 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% -2.624 to 4.062 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.702 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | ANCOVA with randomization Q-LES-Q-SF % maximum total score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.275 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -1.88 | |
| Confidence Interval |
(2-Sided) 95% -5.248 to 1.494 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.716 |
|
| Estimation Comments | ||
| Title | Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form(Q LES-Q-SF)Item 15 |
|---|---|
| Description | The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 15th item queries respondents' satisfaction with the medication they are taking, rated on a 1 to 4 scale, score 0 indicates that no medication was taken. Higher scores are indicative of greater satisfaction. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 142 | 136 | 124 | 138 |
| Least Squares Mean (Standard Error) [units on a scale] |
0.3
(0.08)
|
0.4
(0.08)
|
0.2
(0.08)
|
0.4
(0.08)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 15 score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.412 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.1 | |
| Confidence Interval |
(2-Sided) 95% -0.28 to 0.11 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.10 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 15 score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.928 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -0.19 to 0.21 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.10 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 15 score as covariate, treatment as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.033 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.2 | |
| Confidence Interval |
(2-Sided) 95% -0.42 to -0.02 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.10 |
|
| Estimation Comments | ||
| Title | Change From Randomization (Week 8) to End of Treatment (Week 16) in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q LES-Q-SF) Item 16 |
|---|---|
| Description | The Q-LES-Q-SF (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form) measures the patient's satisfaction with medication and overall quality of life. The 16th item is a global rating of overall life satisfaction and contentment, rated on a 1 to 5 scale. Higher scores are indicative of greater satisfaction. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 152 | 148 | 144 | 151 |
| Least Squares Mean (Standard Error) [units on a scale] |
0.6
(0.08)
|
0.5
(0.08)
|
0.4
(0.08)
|
0.5
(0.08)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 16 as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.353 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.1 | |
| Confidence Interval |
(2-Sided) 95% -0.10 to 0.28 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.10 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 16 as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.721 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -0.16 to 0.23 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.10 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | An analysis of covariance (ANCOVA) with randomization Q-LES-Q-SF item 16 as a fixed effect and pooled center as a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.666 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -0.24 to 0.15 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.10 |
|
| Estimation Comments | ||
| Title | Change in EuroQol - 5 Dimensions (EQ-5D) From Randomization (Week 8) to End of Treatment (Week 16) |
|---|---|
| Description | A self-assessment questionnaire that provides 2 measures of health status. The EQ-5D index score is a weighted linear combination over 5 dimensions of health status. The score for each of the 5 dimensions can range from 1 to 3, and an equation is used to calculate the EQ-5D index score. The EQ-5D index score can range from possible negative values (minimum -0.415) to a maximum of 1.0. The EQ-VAS is a visual analog scale with a range of 0 to 100. For both variables, a higher score indicates a better health state. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 152 | 147 | 147 | 153 |
| EQ-5D index score |
0.114
(0.0169)
|
0.107
(0.0173)
|
0.106
(0.0176)
|
0.120
(0.0168)
|
| EQ-5D VAS score |
13.4
(1.69)
|
12.9
(1.73)
|
10.3
(1.76)
|
11.5
(1.68)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization EQ-5D total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.747 |
| Comments | Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16) | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.006 | |
| Confidence Interval |
(2-Sided) 95% -0.0459 to 0.0329 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.0201 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization EQ-5D total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.524 |
| Comments | Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16) | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.013 | |
| Confidence Interval |
(2-Sided) 95% -0.0529 to 0.0270 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.0203 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization EQ-5D total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.502 |
| Comments | Analysis for change in EQ-5D index score from randomization (Week 8) to end of treatment (Week 16) | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -0.014 | |
| Confidence Interval |
(2-Sided) 95% -0.0543 to 0.0267 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.0206 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization EQ-5D VAS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.345 |
| Comments | Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16) | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 1.9 | |
| Confidence Interval |
(2-Sided) 95% -2.10 to 6.00 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.06 |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization EQ-5D VAS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.486 |
| Comments | Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16) | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 1.5 | |
| Confidence Interval |
(2-Sided) 95% -2.65 to 5.56 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.09 |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit and treatment by visit interaction as explanatory variables and the randomization EQ-5D VAS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.564 |
| Comments | Analysis of change in EQ-5D VAS score from randomization (Week 8) to end of treatment (Week 16) | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -1.2 | |
| Confidence Interval |
(2-Sided) 95% -5.39 to 2.94 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.12 |
|
| Estimation Comments | ||
| Title | Change in Irritability Symptoms as Measured by the Sheehan Irritability Scale (SIS) Total Score From Randomization (Week 8) to End of Treatment (Week 16) |
|---|---|
| Description | A self-administered scale to be used by clinical subjects to rate suffering over the past week with regard to irritability symptoms. The total SIS score is the sum of 7 items, and ranges from 0 to 70. Each item is assessed on an 11- point scale where 0=not at all, 1-3=mildly, 4-6=moderately, 7-9=markedly, and 10=extremely. The SIS also records the number of days impaired by irritability. |
| Time Frame | Randomization (Week 8) to end of treatment (Week 16) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat analysis set including all randomized patients who received at least 1 dose of investigational product (TC-5214 or placebo) and who had a randomization and at least 1 post-randomization MADRS total score. |
| Arm/Group Title | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo BID |
| Measure Participants | 152 | 148 | 149 | 153 |
| Least Squares Mean (Standard Error) [units on a scale] |
-10.2
(1.46)
|
-10.1
(1.49)
|
-8.3
(1.50)
|
-8.8
(1.46)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 0.5 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization SIS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.350 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -1.4 | |
| Confidence Interval |
(2-Sided) 95% -4.48 to 1.59 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.55 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 2 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization SIS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.393 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | -1.3 | |
| Confidence Interval |
(2-Sided) 95% -4.41 to 1.73 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.56 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | 4 mg BID TC-5214, Placebo |
|---|---|---|
| Comments | MMRM model includes treatment, pooled center, visit, and treatment by visit interaction as explanatory variables and the randomization SIS total score as a covariate. Treatment, visit and treatment by visit interaction are fixed effects in the model; pooled center is a random effect. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.745 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean |
| Estimated Value | 0.5 | |
| Confidence Interval |
(2-Sided) 95% -2.59 to 3.62 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.58 |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | ||||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||
| Arm/Group Title | Placebo | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | ||||
| Arm/Group Description | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + Placebo | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 0.5 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 2 mg BID | Selective serotonin reuptake inhibitor (SSRI)/Serotonin/norepinephrine reuptake inhibitor (SNRI) + TC-5214, 4 mg BID | ||||
All Cause Mortality |
||||||||
| Placebo | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||
Serious Adverse Events |
||||||||
| Placebo | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/160 (1.3%) | 2/160 (1.3%) | 0/158 (0%) | 5/158 (3.2%) | ||||
| General disorders | ||||||||
| Non-Cardiac Chest Pain | 1/160 (0.6%) | 1 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 0/158 (0%) | 0 |
| Infections and infestations | ||||||||
| Upper Respiratory Tract Infection | 0/160 (0%) | 0 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 1/158 (0.6%) | 1 |
| Injury, poisoning and procedural complications | ||||||||
| Clavicle Fracture | 0/160 (0%) | 0 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 1/158 (0.6%) | 1 |
| Rib Fracture | 0/160 (0%) | 0 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 1/158 (0.6%) | 1 |
| Scapula Fracture | 0/160 (0%) | 0 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 1/158 (0.6%) | 1 |
| Nervous system disorders | ||||||||
| Convulsion | 0/160 (0%) | 0 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 1/158 (0.6%) | 1 |
| Psychiatric disorders | ||||||||
| Major Depression | 0/160 (0%) | 0 | 1/160 (0.6%) | 1 | 0/158 (0%) | 0 | 1/158 (0.6%) | 1 |
| Suicidal Ideation | 0/160 (0%) | 0 | 1/160 (0.6%) | 1 | 0/158 (0%) | 0 | 0/158 (0%) | 0 |
| Renal and urinary disorders | ||||||||
| Obstructive Uropathy | 0/160 (0%) | 0 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 1/158 (0.6%) | 1 |
| Renal Failure Acute | 0/160 (0%) | 0 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 1/158 (0.6%) | 1 |
| Reproductive system and breast disorders | ||||||||
| Benign Prostatic Hyperplasia | 0/160 (0%) | 0 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 1/158 (0.6%) | 1 |
| Endometriosis | 1/160 (0.6%) | 1 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 0/158 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Pulmonary Fibrosis | 0/160 (0%) | 0 | 1/160 (0.6%) | 1 | 0/158 (0%) | 0 | 0/158 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||
| Placebo | 0.5 mg BID TC-5214 | 2 mg BID TC-5214 | 4 mg BID TC-5214 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 76/160 (47.5%) | 80/160 (50%) | 88/158 (55.7%) | 99/158 (62.7%) | ||||
| Eye disorders | ||||||||
| Vision Blurred | 0/160 (0%) | 0 | 1/160 (0.6%) | 1 | 3/158 (1.9%) | 3 | 6/158 (3.8%) | 7 |
| Gastrointestinal disorders | ||||||||
| Constipation | 7/160 (4.4%) | 8 | 12/160 (7.5%) | 13 | 25/158 (15.8%) | 28 | 45/158 (28.5%) | 48 |
| Nausea | 10/160 (6.3%) | 11 | 7/160 (4.4%) | 7 | 13/158 (8.2%) | 13 | 10/158 (6.3%) | 11 |
| Dry Mouth | 2/160 (1.3%) | 3 | 6/160 (3.8%) | 6 | 11/158 (7%) | 11 | 11/158 (7%) | 11 |
| Diarrhoea | 10/160 (6.3%) | 10 | 10/160 (6.3%) | 11 | 8/158 (5.1%) | 8 | 10/158 (6.3%) | 11 |
| Abdominal Distension | 1/160 (0.6%) | 1 | 2/160 (1.3%) | 2 | 5/158 (3.2%) | 5 | 3/158 (1.9%) | 3 |
| Vomiting | 5/160 (3.1%) | 5 | 1/160 (0.6%) | 1 | 5/158 (3.2%) | 6 | 4/158 (2.5%) | 4 |
| Dyspepsia | 1/160 (0.6%) | 1 | 4/160 (2.5%) | 5 | 2/158 (1.3%) | 2 | 3/158 (1.9%) | 3 |
| Flatulence | 0/160 (0%) | 0 | 2/160 (1.3%) | 2 | 4/158 (2.5%) | 4 | 3/158 (1.9%) | 3 |
| General disorders | ||||||||
| Fatigue | 6/160 (3.8%) | 6 | 2/160 (1.3%) | 2 | 4/158 (2.5%) | 4 | 7/158 (4.4%) | 8 |
| Pyrexia | 1/160 (0.6%) | 2 | 5/160 (3.1%) | 5 | 1/158 (0.6%) | 1 | 0/158 (0%) | 0 |
| Asthenia | 0/160 (0%) | 0 | 1/160 (0.6%) | 1 | 1/158 (0.6%) | 1 | 4/158 (2.5%) | 4 |
| Pain | 3/160 (1.9%) | 3 | 4/160 (2.5%) | 4 | 1/158 (0.6%) | 2 | 3/158 (1.9%) | 3 |
| Infections and infestations | ||||||||
| Nasopharyngitis | 7/160 (4.4%) | 7 | 6/160 (3.8%) | 6 | 7/158 (4.4%) | 8 | 5/158 (3.2%) | 5 |
| Bronchitis | 6/160 (3.8%) | 6 | 0/160 (0%) | 0 | 0/158 (0%) | 0 | 4/158 (2.5%) | 4 |
| Upper Respiratory Tract Infection | 6/160 (3.8%) | 6 | 2/160 (1.3%) | 2 | 6/158 (3.8%) | 6 | 3/158 (1.9%) | 3 |
| Sinusitis | 4/160 (2.5%) | 5 | 2/160 (1.3%) | 2 | 3/158 (1.9%) | 3 | 0/158 (0%) | 0 |
| Aspartate Aminotransferase Increased | 1/160 (0.6%) | 1 | 1/160 (0.6%) | 1 | 4/158 (2.5%) | 4 | 0/158 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||
| Increased Appetite | 1/160 (0.6%) | 1 | 1/160 (0.6%) | 1 | 4/158 (2.5%) | 4 | 2/158 (1.3%) | 2 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Back Pain | 4/160 (2.5%) | 4 | 2/160 (1.3%) | 2 | 2/158 (1.3%) | 2 | 1/158 (0.6%) | 1 |
| Muscle Spasms | 2/160 (1.3%) | 2 | 0/160 (0%) | 0 | 1/158 (0.6%) | 1 | 4/158 (2.5%) | 4 |
| Muscle Tightness | 0/160 (0%) | 0 | 1/160 (0.6%) | 1 | 0/158 (0%) | 0 | 4/158 (2.5%) | 4 |
| Myalgia | 3/160 (1.9%) | 3 | 4/160 (2.5%) | 4 | 3/158 (1.9%) | 3 | 2/158 (1.3%) | 2 |
| Nervous system disorders | ||||||||
| Headache | 22/160 (13.8%) | 25 | 14/160 (8.8%) | 19 | 15/158 (9.5%) | 17 | 13/158 (8.2%) | 14 |
| Dizziness | 3/160 (1.9%) | 3 | 11/160 (6.9%) | 11 | 8/158 (5.1%) | 8 | 14/158 (8.9%) | 14 |
| Somnolence | 5/160 (3.1%) | 5 | 6/160 (3.8%) | 6 | 4/158 (2.5%) | 4 | 8/158 (5.1%) | 8 |
| Dizziness Postural | 2/160 (1.3%) | 2 | 1/160 (0.6%) | 1 | 3/158 (1.9%) | 5 | 5/158 (3.2%) | 7 |
| Akathisia | 4/160 (2.5%) | 4 | 0/160 (0%) | 0 | 3/158 (1.9%) | 3 | 1/158 (0.6%) | 1 |
| Psychiatric disorders | ||||||||
| Insomnia | 9/160 (5.6%) | 10 | 8/160 (5%) | 8 | 8/158 (5.1%) | 8 | 6/158 (3.8%) | 7 |
| Abnormal Dreams | 3/160 (1.9%) | 3 | 2/160 (1.3%) | 2 | 6/158 (3.8%) | 6 | 2/158 (1.3%) | 2 |
| Agitation | 4/160 (2.5%) | 4 | 5/160 (3.1%) | 5 | 4/158 (2.5%) | 4 | 2/158 (1.3%) | 2 |
| Anxiety | 1/160 (0.6%) | 1 | 3/160 (1.9%) | 3 | 4/158 (2.5%) | 4 | 2/158 (1.3%) | 2 |
| Renal and urinary disorders | ||||||||
| Pollakiuria | 0/160 (0%) | 0 | 1/160 (0.6%) | 1 | 0/158 (0%) | 0 | 5/158 (3.2%) | 5 |
| Vascular disorders | ||||||||
| Orthostatic Hypotension | 2/160 (1.3%) | 3 | 1/160 (0.6%) | 1 | 1/158 (0.6%) | 5 | 5/158 (3.2%) | 5 |
| Hypertension | 4/160 (2.5%) | 4 | 3/160 (1.9%) | 3 | 1/158 (0.6%) | 1 | 1/158 (0.6%) | 1 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Gerard Lynch |
|---|---|
| Organization | AstraZeneca |
| Phone | |
| aztrial_results_posting@astrazeneca.com |
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01153347
Other Study ID Numbers:
- D4130C00004
First Posted:
Jun 30, 2010
Last Update Posted:
Apr 11, 2014
Last Verified:
Mar 1, 2014