TRD-2: Study of 6(S)-5-MTHF Among Selective Serotonin Reuptake Inhibitor-Resistant Outpatients With Major Depressive Disorder

• Sponsor: George I. Papakostas (Other)
• Overall Status: Completed
• CT.gov ID: NCT00955955
• Collaborator: Pamlab, L.L.C. (Industry)
• Enrollment: 75
• Locations: 6
• Arms: 3
• Duration (Months): 21
• Patients Per Site: 12.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of the study is to test whether oral 6(S)-5-MTHF (Deplin) is safe and effective in relieving depression when it is added to standard kinds of antidepressants called serotonin reuptake inhibitors (SSRIs).

Condition or Disease	Intervention/Treatment	Phase
Depression	Other: 6(S)-5-MTHF(Deplin); Other: Placebo	Phase 4

Detailed Description

The study consists of two phases, each lasting a total of four weeks (8 weeks total), with visits at the DCRP every 10 days. If the subject is eligible, they will be asked to return two weeks later for a baseline visit, when they will be randomly assigned, like a flip of a coin, to one of three treatment groups: a) drug/drug, b) placebo/drug, c) placebo/placebo (a placebo is a pill that looks like a study drug but contains no active medication). They will have a greater than 50% chance of receiving active medication (Deplin) at some point in the 8 week study.

Neither the subject nor the research staff will know which group the subject is in.

All subjects will be asked to take the study medication in the morning, in addition to their ongoing SSRI treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: TRD - 2: A Double-Blind, Placebo Controlled Study of 6(S)-5-MTHF Among SSRI-Resistant Outpatients With Major Depressive Disorder (MDD)
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 6(S)-5-MTHF(Deplin) Participants will receive 15 mg/day of Deplin, a medical food, for 8 weeks. The SPCD approach, is modified and conducted as follows: The phase II dataset of interest is limited to patients treated with placebo during phase I who completed phase I, who did not experience a clinical response according to the HDRS-17 during phase I and entered phase II. Drug is compared to placebo in phase II for this patient subset alone. The ITT/LOCF data comparing drug and placebo during phase I is combined with the data comparing drug and placebo according to the SPCD model for phase II (see steps 2 and 3 above), and analyzed using the statistical model as described in Fava et al, 2003	Other: 6(S)-5-MTHF(Deplin); Deplin is a medical food. Patients will take 15 mg/day of deplin.
Experimental: Placebo/Deplin Participants will receive placebo for the first 4 weeks, and then 15 mg/day of Deplin (6(S)-5-MTHF) for the next 4 weeks. The SPCD approach, is modified and conducted as follows: The phase II dataset of interest is limited to patients treated with placebo during phase I who completed phase I, who did not experience a clinical response according to the HDRS-17 during phase I and entered phase II. Drug is compared to placebo in phase II for this patient subset alone. The ITT/LOCF data comparing drug and placebo during phase I is combined with the data comparing drug and placebo according to the SPCD model for phase II (see steps 2 and 3 above), and analyzed using the statistical model as described in Fava et al, 2003	Other: 6(S)-5-MTHF(Deplin); Deplin is a medical food. Patients will take 15 mg/day of deplin.; Other: Placebo; Inactive substance
Experimental: Placebo/Placebo Participants will receive placebo for both phases of the study. The SPCD approach, is modified and conducted as follows: The phase II dataset of interest is limited to patients treated with placebo during phase I who completed phase I, who did not experience a clinical response according to the HDRS-17 during phase I and entered phase II. Drug is compared to placebo in phase II for this patient subset alone. The ITT/LOCF data comparing drug and placebo during phase I is combined with the data comparing drug and placebo according to the SPCD model for phase II (see steps 2 and 3 above), and analyzed using the statistical model as described in Fava et al, 2003	Other: Placebo; Inactive substance

Outcome Measures

Primary Outcome Measures

1. The 17-item Hamilton Depression Scale (HAM-D-17) [Baseline and Day 60]

   The HAM-D-17 is a multiple choice questionnaire that clinicians may use to rate the severity of a patient's major depression. Items are scored on a scale of zero to four and higher scores indicate greater impairment. This scale is scored by summing the scores on each item and scores can range from 0-68. When assessing changes in HAMD score, negative changes indicate improvement (i.e. the score has decreased) and positive scores indicate a worsening of symptoms (i.e. scores have increased).

Secondary Outcome Measures

1. The Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) [Baseline and Day 60]

   This measure is a 16 item self report questionnaire assessing symptoms of depression. For each item, scores range from 0 to 3 with higher scores indicating greater impairment. To score this measure: Enter the highest score from questions 1-4 (sleep items): ______ Enter score on item 5 ____ Enter the highest score from questions 6-9 (appetite/weight): ______ Enter score on item 10 ____ Enter score on item 11 ____ Enter score on item 12 ____ Enter score on item 13 ____ Enter score on item 14 ____ Enter the highest score from questions 15-16 (psychomotor items): ______ Total score range 0-27: ______ When assessing changes in this measure over time, negative means indicate an improvement (i.e. the scores decreased over time) and positive means indicate worsening in functioning.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 18-65 years old

• Meet criteria for current Major Depressive Disorder

• Currently taking an SSRI

Exclusion Criteria:

• Pregnant women

• Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease

• Prior course of MTHF augmentation, or intolerance to MTHF at any dose

• Substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past)

• Have failed more than 2 adequate antidepressant trials during the current Major Depressive Episode

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego School of Medicine	San Diego	California	United States	92093
2	Rush University Medical Center, Psychiatric Medicine Associates, LLC	Chicago	Illinois	United States	60612
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	University of Cincinnati, College of Medicine	Cincinnati	Ohio	United States	45221
5	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
6	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• George I. Papakostas
• Pamlab, L.L.C.

Investigators

• Principal Investigator: George I. Papakostas, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: George I. Papakostas, Director of Treatment Resistant Depression Studies-DCRP, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00955955
• Other Study ID Numbers: 2006P000604 (2)
• First Posted: Aug 10, 2009
• Last Update Posted: Apr 28, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by George I. Papakostas, Director of Treatment Resistant Depression Studies-DCRP, Massachusetts General Hospital: Depression; Medical food
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major

Study Results

Participant Flow

Arm/Group Title	Deplin/Deplin	Placebo/Deplin	Placebo/Placebo
Arm/Group Description	Participants will receive 15 mg/day of Deplin (6(S)-5-MTHF) for 8 weeks.	Participants will receive placebo for the first 4 weeks, and then 15 mg/day of Deplin (6(S)-5-MTHF) for the next 4 weeks.	Both tablets of study medication will be placebo during both phases of the study.
Period Title: Overall Study
STARTED	19	28	28
COMPLETED	17	28	28
NOT COMPLETED	2	0	0

Baseline Characteristics

Arm/Group Title	Deplin/Deplin	Placebo/Deplin	Placebo/Placebo	Total
Arm/Group Description	Participants will receive 15 mg/day of Deplin (6(S)-5-MTHF) for 8 weeks.	Participants will receive placebo for the first 4 weeks, and then 15 mg/day of Deplin (6(S)-5-MTHF) for the next 4 weeks.	Both tablets of study medication will be placebo during both phases of the study.	Total of all reporting groups
Overall Participants	19	28	28	75
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	18 94.7%	28 100%	28 100%	74 98.7%
>=65 years	1 5.3%	0 0%	0 0%	1 1.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.58 (14.64)	50.86 (10.58)	45.39 (11.60)	48.49 (12.17)
Sex: Female, Male (Count of Participants)
Female	14 73.7%	19 67.9%	20 71.4%	53 70.7%
Male	5 26.3%	9 32.1%	8 28.6%	22 29.3%
Region of Enrollment (participants) [Number]
United States	19 100%	28 100%	28 100%	75 100%

Outcome Measures

1. Primary Outcome

Title	The 17-item Hamilton Depression Scale (HAM-D-17)
Description	The HAM-D-17 is a multiple choice questionnaire that clinicians may use to rate the severity of a patient's major depression. Items are scored on a scale of zero to four and higher scores indicate greater impairment. This scale is scored by summing the scores on each item and scores can range from 0-68. When assessing changes in HAMD score, negative changes indicate improvement (i.e. the score has decreased) and positive scores indicate a worsening of symptoms (i.e. scores have increased).
Time Frame	Baseline and Day 60

Outcome Measure Data

Analysis Population Description

The phase II dataset of interest is limited to patients treated with placebo in phase I, completed phase I, did not experience a clinical response and entered phase II. Drug is compared to placebo in phase II for this subset alone. Some patients received Deplin in both phases of the study, but those patients are not included in these analyses.

Arm/Group Title	Adjunct 6(S)-5-MTHF(Deplin) Phase 1	Adjunct Placebo Phase 1	Adjunct 6(S)-5-MTHF(Deplin) Phase 2	Adjunct Placebo Phase 2	Pooled Deplin	Pooled Placebo
Arm/Group Description	Participants will receive 15 mg/day of Deplin (6(S)-5-MTHF) for 4 weeks.	Participants will receive placebo for the first 4 weeks	Participants will receive 15 mg of Deplin (6(S)-5-MTHF) for 4 weeks.	Patients in this group received placebo in both phases of the study for a total of 8 weeks,	Patients in this group received Deplin at some point during the study. Results are pooled from phase I and II.	Patients in this group received placebo at some point during the study. Results are pooled from phase I and II.
Measure Participants	19	56	18	21	36	75
Mean (Standard Deviation) [Scores on a scale]	-7.4 (5.2)	-4.4 (5.8)	-3.8 (6.2)	-1.7 (4.7)	-5.58 (5.7)	-3.04 (5.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pooled Deplin, Pooled Placebo
	Comments	Hypothesis 1: There will be a statistically significant difference between the two groups in the degree of improvement, as measured by the change in the 17-item Hamilton Depression Rating Scale (HAM-D-17) score from baseline to endpoint, using the sequential parallel comparison design [51]; with a greater degree of reduction in HAM-D-17 scores in the 6(S)-5-MTHF 15 mg qd group than in the placebo group, with the change on placebo being estimated from Trials 1 and 2.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.05
	Comments
	Method	SPCD
	Comments	Sequential Parallel Comparison Design (SPCD)
Method of Estimation	Estimation Parameter	Mean Score Reduction
	Estimated Value	-5.6
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Deviation; Value: 5.7
	Estimation Comments	These results reflect the mean score reduction for the pooled Deplin sample.

2. Secondary Outcome

Title	The Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR)
Description	This measure is a 16 item self report questionnaire assessing symptoms of depression. For each item, scores range from 0 to 3 with higher scores indicating greater impairment. To score this measure: Enter the highest score from questions 1-4 (sleep items): ______ Enter score on item 5 ____ Enter the highest score from questions 6-9 (appetite/weight): ______ Enter score on item 10 ____ Enter score on item 11 ____ Enter score on item 12 ____ Enter score on item 13 ____ Enter score on item 14 ____ Enter the highest score from questions 15-16 (psychomotor items): ______ Total score range 0-27: ______ When assessing changes in this measure over time, negative means indicate an improvement (i.e. the scores decreased over time) and positive means indicate worsening in functioning.
Time Frame	Baseline and Day 60

Outcome Measure Data

Analysis Population Description

Data presented is mean score reduction for the QIDS. The dataset of interest is limited to patients treated with placebo in phase I, did not experience a clinical response and entered phase II. Drug is compared to placebo in phase II for this subset alone.

Arm/Group Title	Adjunct 6(S)-5-MTHF(Deplin) Phase I	Adjunct Placebo Phase I	Adjunct 6(S)-5-MTHF(Deplin) Phase II	Adjunct Placebo Phase II
Arm/Group Description	Patients who received Deplin (L-methylfolate) for 4 weeks	Patients who received placebo for 4 weeks.	Patients received Deplin for 4 weeks.	Patients received placebo for the second 4 weeks of the study. Patients who received placebo in phase 2 also received it in phase 1.
Measure Participants	19	56	18	21
Mean (Standard Deviation) [Scores on a scale]	-8.1 (5.3)	-5.7 (5.6)	-1.3 (4.9)	0.5 (5.0)

Adverse Events

Time Frame	60 days
Adverse Event Reporting Description	Adverse events data was collected using the SAFTEE measure. Adverse events are reported across both phases of the study. They reflect the number of people who took either medication at any point in the study, not the total number of study participants.
Arm/Group Title	Deplin		Placebo
Arm/Group Description	Participants will receive 15 mg/day of Deplin (6(S)-5-MTHF).		Adverse events for participants who received placebo during the study.
All Cause Mortality
	Deplin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Deplin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/54 (0%)
Other (Not Including Serious) Adverse Events
	Deplin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/42 (57.1%)		48/54 (88.9%)
Gastrointestinal disorders
Gastrointestinal	7/42 (16.7%)	12	8/54 (14.8%)	23
General disorders
Sleep	1/42 (2.4%)	5	3/54 (5.6%)	12
Somatic	6/42 (14.3%)	12	16/54 (29.6%)	22
Miscellaneous	1/42 (2.4%)	3	5/54 (9.3%)	5
Infections and infestations
Infectious	5/42 (11.9%)	8	7/54 (13%)	13
Psychiatric disorders
Psychological	4/42 (9.5%)	4	9/54 (16.7%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.