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

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ClinicalTrials.gov Identifier: NCT00955955
Recruitment Status : Completed
First Posted : August 10, 2009
Results First Posted : January 18, 2013
Last Update Posted : April 28, 2017
Sponsor:
Collaborator:
Pamlab, L.L.C.
Information provided by (Responsible Party):
George I. Papakostas, Massachusetts General Hospital

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Depression
Interventions Other: 6(S)-5-MTHF(Deplin)
Other: Placebo
Enrollment 75
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Deplin/Deplin Placebo/Deplin Placebo/Placebo
Hide 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
Reason Not Completed
Lost to Follow-up             2             0             0
Arm/Group Title Deplin/Deplin Placebo/Deplin Placebo/Placebo Total
Hide 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 Number of Baseline Participants 19 28 28 75
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 28 participants 28 participants 75 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
18
  94.7%
28
 100.0%
28
 100.0%
74
  98.7%
>=65 years
1
   5.3%
0
   0.0%
0
   0.0%
1
   1.3%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 19 participants 28 participants 28 participants 75 participants
49.58  (14.64) 50.86  (10.58) 45.39  (11.60) 48.49  (12.17)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 28 participants 28 participants 75 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  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 19 participants 28 participants 28 participants 75 participants
19 28 28 75
1.Primary Outcome
Title The 17-item Hamilton Depression Scale (HAM-D-17)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 19 56 18 21 36 75
Mean (Standard Deviation)
Unit of Measure: 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)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value .05
Comments [Not Specified]
Method SPCD
Comments Sequential Parallel Comparison Design (SPCD)
Method of Estimation Estimation Parameter Mean Score Reduction
Estimated Value -5.6
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)
Hide 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:

  1. Enter the highest score from questions 1-4 (sleep items): ______
  2. Enter score on item 5 ____
  3. Enter the highest score from questions 6-9 (appetite/weight): ______
  4. Enter score on item 10 ____
  5. Enter score on item 11 ____
  6. Enter score on item 12 ____
  7. Enter score on item 13 ____
  8. Enter score on item 14 ____
  9. 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 19 56 18 21
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
-8.1  (5.3) -5.7  (5.6) -1.3  (4.9) 0.5  (5.0)
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
Hide 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 (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Deplin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/42 (0.00%)      0/54 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Deplin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   24/42 (57.14%)      48/54 (88.89%)    
Gastrointestinal disorders     
Gastrointestinal   7/42 (16.67%)  12 8/54 (14.81%)  23
General disorders     
Sleep   1/42 (2.38%)  5 3/54 (5.56%)  12
Somatic   6/42 (14.29%)  12 16/54 (29.63%)  22
Miscellaneous   1/42 (2.38%)  3 5/54 (9.26%)  5
Infections and infestations     
Infectious   5/42 (11.90%)  8 7/54 (12.96%)  13
Psychiatric disorders     
Psychological   4/42 (9.52%)  4 9/54 (16.67%)  12
Indicates events were collected by systematic assessment
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.
Results Point of Contact
Name/Title: Dr. George Papakostas- Director of Treatment Resistant Depression Studies
Organization: Massachusetts General Hospital- Depression Clinical and Research Program
Phone: 617-726-6697
Responsible Party: George I. Papakostas, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00955955     History of Changes
Other Study ID Numbers: 2006P000604 (2)
First Submitted: July 30, 2009
First Posted: August 10, 2009
Results First Submitted: October 31, 2012
Results First Posted: January 18, 2013
Last Update Posted: April 28, 2017