A Study to Evaluate the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Major Depressive Disorder

• Sponsor: Taisho Pharmaceutical R&D Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03093025
• Collaborator: (none)
• Enrollment: 51
• Locations: 22
• Arms: 3
• Actual Duration (Months): 17.1
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, and efficacy of TS-121 as an adjunctive treatment for patients with major depressive disorder with an inadequate response to current antidepressant Treatment (SSRI, SNRI or bupropion).

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: TS-121 10 mg; Drug: TS-121 50 mg; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Patients With Major Depressive Disorder With an Inadequate Response to Current Antidepressant Treatment
• Actual Study Start Date: Jul 3, 2017
• Actual Primary Completion Date: Nov 8, 2018
• Actual Study Completion Date: Dec 4, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TS-121 10mg	Drug: TS-121 10 mg; Orally taken once daily
Experimental: TS-121 50mg	Drug: TS-121 50 mg; Orally taken once daily
Placebo Comparator: Placebo	Drug: Placebo; Orally taken once daily

Outcome Measures

Primary Outcome Measures

1. Montgomery-Asberg Depression Rating Scale (MADRS) [6 weeks]

   The MADRS is a clinician-rated scale to assess depressive symptoms which consists from 10 items. The time frame for this scale is the past 7 days. Each item is scored on 7-point scale (0 [absence of symptoms] to 6 [severe]). The total score is the sum of 10 items and can take range from 0 to 60. A negative change from baseline indicates improvement.

Secondary Outcome Measures

1. Hamilton Anxiety Scale (HAM-A) [6 weeks]

   The HAM-A is a clinician-rated scale to assess anxiety symptoms which consists from 14 items. The time frame for this scale is the past 7 days. Each item is scored on 5-point scale (0 [absence of symptoms] to 4 [severe]). The total score is the sum of 14 items and can take range from 0 to 56. A negative change from baseline indicates improvement.

2. Symptoms of Depression Questionnaire (SDQ) [6 weeks]

   The SDQ is a self-rated scale to assess the severity of symptoms across several subtypes of depression which consists from 44 items. The time frame for this scale is the past 7 days. Each item is scored on 6-point scale (1 [better than normal] to 6 [severe]). The total score is the sum of 44 items and can take range from 44 to 264. A negative change from baseline indicates improvement.

3. Clinical Global Impression-Severity (CGI-S) [6 weeks]

   The CGI-S is a clinician-rated scale to assess the severity of the disorder. The time frame for this scale is the past 7 days. The score ranges from 1 (Normal, not ill at all) to 7 (Among the most extremely ill patients).

4. Montgomery-Asberg Depression Rating Scale (MADRS) [6 weeks]

   Percentage of MADRS responders (≥ 50% reduction in total score) at Week 6

5. Clinical Global Impression-Improvement (CGI-I) [6 weeks]

   Percentage of CGI-I improvers ("Very much improved" or "Much improved") at Week 6

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Adult males and females between 18 and 65 years of age inclusive (at time of initial informed consent)

2. Patients with a current diagnosis of MDD by DSM-5, confirmed through a structured interview using MINI

3. Patients who receive the same antidepressant (SSRI, SNRI or bupropion monotherapy) for at least 6 weeks of continuous treatment with at least 4 weeks on a fixed dose

4. Patients who willing to remain on the same primary SSRI, SNRI or bupropion and fixed dose throughout the course of the study

5. Patients who meet the total score on the HAM-D as listed below

6. HAM-D ≥ 18 at Screening

7. HAM-D ≥ 18 at Baseline

8. Body Mass Index (BMI) ≥ 18 and ≤ 38 kg/m2

Exclusion Criteria:

1. Patients with inadequate response to ≥2 prior antidepressant treatments (not including current antidepressant) of at least 4 weeks duration each for the current episode

2. Patients whose current depressive episode is diagnosed with psychotic features, catatonic features, post-partum (primary onset), or is secondary to a general medical disorder

3. Patients with a diagnosis of any of the following DSM-5 class disorders

4. Schizophrenia spectrum and other psychotic disorders

5. Bipolar and related disorders

6. Anxiety disorders [Co-morbid GAD and SAD will be allowed in the study if the primary diagnosis is MDD, and if in the opinion of the investigator, the comorbid anxiety is not likely to interfere with the subject's ability to participate in the trial or affect study outcome]

7. Obsessive-compulsive and related disorders

8. Trauma- and Stressor-related disorders

9. Patients who received electroconvulsive therapy (ECT) within 12 months of Screening, received more than one course of ECT in their lifetime or plan to receive ECT during the study

10. Patients who received repetitive transcranial magnetic stimulation (rTMS) within 12 months of Screening or plan to receive rTMS during the study

11. Patients who plan to initiate or terminate cognitive or behavioral psychotherapy or alter the frequency of ongoing therapy during this study

12. Patients who have attempted suicide within the past 6 months

13. Patients with history or presence of intellectual disability, pervasive developmental disorder, cognitive disorder, neurodegenerative disorder, or brain injury

14. Patients with any history or complication of convulsive disorder

15. Patients who are undergoing treatment with psychotropic medications, benzodiazepines, metyrapone, lithium and/or corticosteroids

16. Patients who are taking moderate to strong CYP3A4 inhibitors/inducers

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Woodland International Research Group	Little Rock	Arkansas	United States	72211
2	Woodland Research Northwest	Rogers	Arkansas	United States	72758
3	Collaborative Neuroscience Network	Garden Grove	California	United States	92845
4	PAREXEL Early Phase Clinical Unit	Glendale	California	United States	91206
5	Synergy East	Lemon Grove	California	United States	91945
6	NRC Research Institute	Orange	California	United States	92868
7	MCB Clinical Research Centers	Colorado Springs	Colorado	United States	80910
8	Comprehensive Psychiatric Care	Norwich	Connecticut	United States	06360
9	Compass Research	Orlando	Florida	United States	32806
10	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
11	Rush University Medical Center	Chicago	Illinois	United States	60612
12	Chicago Research Center	Chicago	Illinois	United States	60634
13	Alexian Brothers Behavioral Health Hospital	Hoffman Estates	Illinois	United States	60169
14	Boston Clinical Trials	Boston	Massachusetts	United States	02131
15	Midwest Research Group - St. Charles Psychiatric Associates	Saint Charles	Missouri	United States	63304
16	St. Louis Clinical Trials	Saint Louis	Missouri	United States	63141
17	Hassman Research Institute	Berlin	New Jersey	United States	08009
18	Global Medical Institutes	Princeton	New Jersey	United States	08540
19	SPRI Clinical Trials	Brooklyn	New York	United States	11235
20	Midwest Clinical Research Center	Dayton	Ohio	United States	45417
21	IPS Research Company	Oklahoma City	Oklahoma	United States	73103
22	Grayline Clinical Drug Trials	Wichita Falls	Texas	United States	76309

Sponsors and Collaborators

• Taisho Pharmaceutical R&D Inc.

Investigators

• Study Chair: Shoji Yasuda, Taisho Pharmaceutical R&D Inc.

Study Documents (Full-Text)

• Study Protocol - Apr 23, 2018
• Statistical Analysis Plan - Dec 18, 2018

More Information

Additional Information:

• Related Info

Publications

• Kamiya M, Sabia HD, Marella J, Fava M, Nemeroff CB, Umeuchi H, Iijima M, Chaki S, Nishino I. Efficacy and safety of TS-121, a novel vasopressin V(1B) receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study. J Psychiatr Res. 2020 Sep;128:43-51. doi: 10.1016/j.jpsychires.2020.05.017. Epub 2020 May 31.

• Responsible Party: Taisho Pharmaceutical R&D Inc.
• ClinicalTrials.gov Identifier: NCT03093025
• Other Study ID Numbers: TS121-US201
• First Posted: Mar 28, 2017
• Last Update Posted: Jul 14, 2020
• Last Verified: Jul 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Taisho Pharmaceutical R&D Inc.: Major Depressive Disorder; Adjunctive Treatment
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major

Study Results

Participant Flow

Arm/Group Title	TS-121 10mg	TS-121 50mg	Placebo
Arm/Group Description	TS-121 10 mg: Orally taken once daily	TS-121 50 mg: Orally taken once daily	Placebo: Orally taken once daily
Period Title: Overall Study
STARTED	16	17	18
COMPLETED	12	15	16
NOT COMPLETED	4	2	2

Baseline Characteristics

Arm/Group Title	TS-121 10mg	TS-121 50mg	Placebo	Total
Arm/Group Description	TS-121 10 mg: Orally taken once daily	TS-121 50 mg: Orally taken once daily	Placebo: Orally taken once daily	Total of all reporting groups
Overall Participants	16	16	18	50
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.8 (12.62)	44.8 (12.93)	45.8 (11.09)	45.1 (11.95)
Sex: Female, Male (Count of Participants)
Female	10 62.5%	11 68.8%	12 66.7%	33 66%
Male	6 37.5%	5 31.3%	6 33.3%	17 34%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	3 18.8%	1 6.3%	2 11.1%	6 12%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	6 37.5%	4 25%	3 16.7%	13 26%
White	7 43.8%	10 62.5%	12 66.7%	29 58%
More than one race	0 0%	1 6.3%	1 5.6%	2 4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Montgomery-Asberg Depression Rating Scale (MADRS)
Description	The MADRS is a clinician-rated scale to assess depressive symptoms which consists from 10 items. The time frame for this scale is the past 7 days. Each item is scored on 7-point scale (0 [absence of symptoms] to 6 [severe]). The total score is the sum of 10 items and can take range from 0 to 60. A negative change from baseline indicates improvement.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Participants who did not receive at least one dose of investigational product or did not have at least one post-dose assessments were not included in the analysis.

Arm/Group Title	TS-121 10mg	TS-121 50mg	Placebo
Arm/Group Description	TS-121 10 mg: Orally taken once daily	TS-121 50 mg: Orally taken once daily	Placebo: Orally taken once daily
Measure Participants	13	15	17
Least Squares Mean (95% Confidence Interval) [score on a scale]	-9.0	-9.0	-6.4

2. Secondary Outcome

Title	Hamilton Anxiety Scale (HAM-A)
Description	The HAM-A is a clinician-rated scale to assess anxiety symptoms which consists from 14 items. The time frame for this scale is the past 7 days. Each item is scored on 5-point scale (0 [absence of symptoms] to 4 [severe]). The total score is the sum of 14 items and can take range from 0 to 56. A negative change from baseline indicates improvement.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Participants who did not receive at least one dose of investigational product or did not have at least one post-dose assessments were not included in the analysis.

Arm/Group Title	TS-121 10mg	TS-121 50mg	Placebo
Arm/Group Description	TS-121 10 mg: Orally taken once daily	TS-121 50 mg: Orally taken once daily	Placebo: Orally taken once daily
Measure Participants	13	15	17
Least Squares Mean (95% Confidence Interval) [score on a scale]	-5.6	-3.4	-2.8

3. Secondary Outcome

Title	Symptoms of Depression Questionnaire (SDQ)
Description	The SDQ is a self-rated scale to assess the severity of symptoms across several subtypes of depression which consists from 44 items. The time frame for this scale is the past 7 days. Each item is scored on 6-point scale (1 [better than normal] to 6 [severe]). The total score is the sum of 44 items and can take range from 44 to 264. A negative change from baseline indicates improvement.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Participants who did not receive at least one dose of investigational product or did not have at least one post-dose assessments were not included in the analysis.

Arm/Group Title	TS-121 10mg	TS-121 50mg	Placebo
Arm/Group Description	TS-121 10 mg: Orally taken once daily	TS-121 50 mg: Orally taken once daily	Placebo: Orally taken once daily
Measure Participants	13	15	17
Least Squares Mean (95% Confidence Interval) [score on a scale]	-22.5	-17.0	-13.7

4. Secondary Outcome

Title	Clinical Global Impression-Severity (CGI-S)
Description	The CGI-S is a clinician-rated scale to assess the severity of the disorder. The time frame for this scale is the past 7 days. The score ranges from 1 (Normal, not ill at all) to 7 (Among the most extremely ill patients).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Participants who did not receive at least one dose of investigational product or did not have at least one post-dose assessments were not included in the analysis.

Arm/Group Title	TS-121 10mg	TS-121 50mg	Placebo
Arm/Group Description	TS-121 10 mg: Orally taken once daily	TS-121 50 mg: Orally taken once daily	Placebo: Orally taken once daily
Measure Participants	13	15	17
Least Squares Mean (95% Confidence Interval) [score on a scale]	-0.8	-0.7	-0.5

5. Secondary Outcome

Title	Montgomery-Asberg Depression Rating Scale (MADRS)
Description	Percentage of MADRS responders (≥ 50% reduction in total score) at Week 6
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TS-121 10mg	TS-121 50mg	Placebo
Arm/Group Description	TS-121 10 mg: Orally taken once daily	TS-121 50 mg: Orally taken once daily	Placebo: Orally taken once daily
Measure Participants	12	15	16
Number [percentage of participants]	33.3 208.1%	20.0 125%	12.5 69.4%

6. Secondary Outcome

Title	Clinical Global Impression-Improvement (CGI-I)
Description	Percentage of CGI-I improvers ("Very much improved" or "Much improved") at Week 6
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TS-121 10mg	TS-121 50mg	Placebo
Arm/Group Description	TS-121 10 mg: Orally taken once daily	TS-121 50 mg: Orally taken once daily	Placebo: Orally taken once daily
Measure Participants	12	15	16
Number [percentage of participants]	33.3 208.1%	26.7 166.9%	18.8 104.4%

Adverse Events

Time Frame	Onset date on or later than date of first dose of the randomized treatment through follow-up visit, an average of 8 weeks.
Adverse Event Reporting Description	One participant in TS-121 50 mg group did not take any dose of investigational product after randomization. Therefore, the participant was not included in analyses.
Arm/Group Title	TS-121 10mg		TS-121 50mg		Placebo
Arm/Group Description	TS-121 10 mg: Orally taken once daily		TS-121 50 mg: Orally taken once daily		Placebo: Orally taken once daily
All Cause Mortality
	TS-121 10mg		TS-121 50mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/18 (0%)
Serious Adverse Events
	TS-121 10mg		TS-121 50mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	TS-121 10mg		TS-121 50mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/16 (43.8%)		7/16 (43.8%)		8/18 (44.4%)
Blood and lymphatic system disorders
Anaemia	0/16 (0%)	0	0/16 (0%)	0	1/18 (5.6%)	1
Ear and labyrinth disorders
Tinnitus	0/16 (0%)	0	1/16 (6.3%)	1	2/18 (11.1%)	2
Eye disorders
Diplopia	1/16 (6.3%)	1	0/16 (0%)	0	0/18 (0%)	0
Eyelid oedema	0/16 (0%)	0	1/16 (6.3%)	1	0/18 (0%)	0
Lenticular opacities	0/16 (0%)	0	2/16 (12.5%)	2	0/18 (0%)	0
Vision blurred	1/16 (6.3%)	1	0/16 (0%)	0	0/18 (0%)	0
Gastrointestinal disorders
Constipation	1/16 (6.3%)	1	0/16 (0%)	0	0/18 (0%)	0
Nausea	1/16 (6.3%)	1	0/16 (0%)	0	1/18 (5.6%)	1
General disorders
Oedema peripheral	0/16 (0%)	0	1/16 (6.3%)	1	0/18 (0%)	0
Infections and infestations
Cellulitis	1/16 (6.3%)	1	0/16 (0%)	0	0/18 (0%)	0
Gastroenteritis viral	0/16 (0%)	0	0/16 (0%)	0	1/18 (5.6%)	1
Haemorrhoid infection	0/16 (0%)	0	0/16 (0%)	0	1/18 (5.6%)	1
Influenza	1/16 (6.3%)	1	0/16 (0%)	0	1/18 (5.6%)	1
Localised infection	0/16 (0%)	0	1/16 (6.3%)	1	0/18 (0%)	0
Upper respiratory tract infection	0/16 (0%)	0	0/16 (0%)	0	2/18 (11.1%)	2
Urinary tract infection	0/16 (0%)	0	2/16 (12.5%)	2	0/18 (0%)	0
Injury, poisoning and procedural complications
Arthropod bite	0/16 (0%)	0	1/16 (6.3%)	1	0/18 (0%)	0
Medication error	1/16 (6.3%)	1	1/16 (6.3%)	2	0/18 (0%)	0
Investigations
Bacterial test positive	0/16 (0%)	0	1/16 (6.3%)	1	0/18 (0%)	0
Blood creatinine increased	0/16 (0%)	0	0/16 (0%)	0	1/18 (5.6%)	1
Crystal urine present	0/16 (0%)	0	1/16 (6.3%)	1	0/18 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	1/16 (6.3%)	1	0/16 (0%)	0	0/18 (0%)	0
Nervous system disorders
Disturbance in attention	0/16 (0%)	0	1/16 (6.3%)	1	0/18 (0%)	0
Dizziness	0/16 (0%)	0	1/16 (6.3%)	1	0/18 (0%)	0
Headache	1/16 (6.3%)	1	1/16 (6.3%)	1	0/18 (0%)	0
Paraesthesia	0/16 (0%)	0	0/16 (0%)	0	1/18 (5.6%)	1
Psychiatric disorders
Depression	0/16 (0%)	0	0/16 (0%)	0	1/18 (5.6%)	1
Renal and urinary disorders
Nephrolithiasis	0/16 (0%)	0	1/16 (6.3%)	1	0/18 (0%)	0
Skin and subcutaneous tissue disorders
Ingrowing nail	0/16 (0%)	0	0/16 (0%)	0	1/18 (5.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.