Transcranial Laser Therapy, Continuous and Pulsed Light, for Major Depressive Disorder (ELATED-3) (ELATED-3)

• ClinicalTrials.gov Identifier: NCT02959307
• Recruitment Status: Completed
• First Posted: November 9, 2016
• Results First Posted: September 21, 2020
• Last Update Posted: September 21, 2020
• Sponsor: Massachusetts General Hospital
• Collaborator: LiteCure LLC
• Information provided by (Responsible Party): Paolo Cassano, Massachusetts General Hospital

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Conditions: Depression; Major Depressive Disorder
• Interventions: Device: Transcranial Light Therapy; Device: Sham Transcranial Light Therapy
• Enrollment: 49

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Transcranial Light Therapy	Sham Transcranial Light Therapy
Arm/Group Description	Transcranial light therapy penetrates the skin and brain using light energy and, the light energy may activate under-stimulated brain regions. Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions.	For the sham group, The transcranial light therapy device uses nonpenetrating light emitting diode light energy. The sham controls for which participants improve from the actual transcranial light therapy treatment and which participants improve during the study for reasons other than the therapy Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions. Sham Transcranial Light Therapy: The same device used for the actual transcranial light therapy is used as the sham device; The device, when set to sham, will mimic the actual transcranial light therapy; however, when set to sham the device does not emit skin and cranium penetrating light emitting diode light energy.
Period Title: Phase 1
Started	18	31
Completed	15	23
Not Completed	3	8
Period Title: Phase 2
Started	28 [1]	10 [2]
Completed	26	10
Not Completed	2	0
[1] This group is increased as those in sham were re-randomized to sham or NIR.; [2] This group is decreased as those in sham were re-randomized to sham or NIR.

Baseline Characteristics

Arm/Group Title		Transcranial Light Therapy	Sham Transcranial Light Therapy	Total
Arm/Group Description		Transcranial light therapy penetrates the skin and brain using light energy and, the light energy may activate under-stimulated brain regions. Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions.	For the sham group, The transcranial light therapy device uses nonpenetrating light emitting diode light energy. The sham controls for which participants improve from the actual transcranial light therapy treatment and which participants improve during the study for reasons other than the therapy Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions. Sham Transcranial Light Therapy: The same device used for the actual transcranial light therapy is used as the sham device; The device, when set to sham, will mimic the actual transcranial light therapy; however, when set to sham the device does not emit skin and cranium penetrating light emitting diode light energy.	Total of all reporting groups
Overall Number of Baseline Participants		18	31	49
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	18 participants	31 participants	49 participants
		37.222 (15.509)	42.806 (15.823)	40.755 (16.137)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	18 participants	31 participants	49 participants
	Female	14 77.8%	21 67.7%	35 71.4%
	Male	4 22.2%	10 32.3%	14 28.6%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	18 participants	31 participants	49 participants
	Hispanic or Latino	1 5.6%	2 6.5%	3 6.1%
	Not Hispanic or Latino	15 83.3%	25 80.6%	40 81.6%
	Unknown or Not Reported	2 11.1%	4 12.9%	6 12.2%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	18 participants	31 participants	49 participants
	American Indian or Alaska Native	0 0.0%	1 3.2%	1 2.0%
	Asian	2 11.1%	1 3.2%	3 6.1%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	2 11.1%	2 6.5%	4 8.2%
	White	13 72.2%	27 87.1%	40 81.6%
	More than one race	1 5.6%	0 0.0%	1 2.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Age of Depressive Onset [1]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	18 participants	31 participants	49 participants
		17.294 (9.973)	23.429 (16.089)	21.111 (14.285)
		[1] Measure Description: Participants were asked when they first remembered onset of depressive symptoms. Some participants had trouble recollecting. Analysis was only performed on participants who had definitive age of onset.

Outcome Measures

1. Primary Outcome

Title	Quick Inventory of Depressive Symptomatology-Phase 1
Description	This is a brief (16-item) clinician-rated inventory of core depressive symptoms such as sleep, depressed mood, appetite, concentration, suicidal ideation, interest, energy, psychomotor retardation or agitation. Scores range from 0-27, higher scores indicating greater depression severity.
Time Frame	6 weeks - Sequential-parallel comparison design

Outcome Measure Data

Analysis Population Description

Sham Group in Phase 1 accounts for all subjects Receiving Sham. Patients in Sham within the first phase would be re-randomized to either NIR or Sham after completion of the initial 6 weeks. 2 participants in Sham did not have scores collected, as such the Sham group for Phase 1 consists of 29 participants rather than the total 31.

Arm/Group Title	Transcranial Light Therapy	Sham Transcranial Light Therapy
Arm/Group Description:	Transcranial light therapy penetrates the skin and brain using light energy and, the light energy may activate under-stimulated brain regions. Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions.	For the sham group, The transcranial light therapy device uses nonpenetrating light emitting diode light energy. The sham controls for which participants improve from the actual transcranial light therapy treatment and which participants improve during the study for reasons other than the therapy Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions. Sham Transcranial Light Therapy: The same device used for the actual transcranial light therapy is used as the sham device; The device, when set to sham, will mimic the actual transcranial light therapy; however, when set to sham the device does not emit skin and cranium penetrating light emitting diode light energy.
Overall Number of Participants Analyzed	18	29
Mean (Standard Deviation); Unit of Measure: score on a scale
	11.06 (3.78)	11.24 (4.83)

2. Primary Outcome

Title	Quick Inventory of Depressive Symptomatology(QIDS)-Phase 2
Description	This is a brief (16-item) clinician-rated inventory of core depressive symptoms such as sleep, depressed mood, appetite, concentration, suicidal ideation, interest, energy, psychomotor retardation or agitation. Scores range from 0-27, higher scores indicating greater depression severity.
Time Frame	6 weeks - Sequential-parallel comparison design

Outcome Measure Data

Analysis Population Description

This group consists of all sham participants that did not respond to Sham in Phase 1 and were re-randomized into Phase 2. Therefore, of the 29 participants in Sham, 5 participants were responders, 4 were not re-randomized.

Arm/Group Title	Transcranial Light Therapy	Sham Transcranial Light Therapy
Arm/Group Description:	Transcranial light therapy penetrates the skin and brain using light energy and, the light energy may activate under-stimulated brain regions. Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions.	For the sham group, The transcranial light therapy device uses nonpenetrating light emitting diode light energy. The sham controls for which participants improve from the actual transcranial light therapy treatment and which participants improve during the study for reasons other than the therapy Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions. Sham Transcranial Light Therapy: The same device used for the actual transcranial light therapy is used as the sham device; The device, when set to sham, will mimic the actual transcranial light therapy; however, when set to sham the device does not emit skin and cranium penetrating light emitting diode light energy.
Overall Number of Participants Analyzed	11	7
Mean (Standard Deviation); Unit of Measure: score on a scale
	10.45 (5.751)	9.14 (5.551)

3. Secondary Outcome

Title	Hamilton Depression Rating Scale - 17 Items(Phase 1)
Description	assessment of the patient's depressive symptoms, using a structured interview and defined anchor points. The Hamilton Depression Rating Scale aims to quantify the degree of depression in patients who already have a diagnosis of major depression. Score ranges from 0-52. Higher score indicates greater severity of depression.
Time Frame	6 weeks - Sequential-parallel comparison design

Outcome Measure Data

Analysis Population Description

Patients in Sham within the first phase would be re-randomized to either NIR or Sham after completion of the initial 6 weeks. There were two participants in the Sham group who did not have scores for the primary analysis (QIDS), we decided to include them in the secondary analysis (HAMD) as they had scores.

Arm/Group Title	Transcranial Light Therapy	Sham Transcranial Light Therapy
Arm/Group Description:	Transcranial light therapy penetrates the skin and brain using light energy and, the light energy may activate under-stimulated brain regions. Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions.	For the sham group, The transcranial light therapy device uses nonpenetrating light emitting diode light energy. The sham controls for which participants improve from the actual transcranial light therapy treatment and which participants improve during the study for reasons other than the therapy Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions. Sham Transcranial Light Therapy: The same device used for the actual transcranial light therapy is used as the sham device; The device, when set to sham, will mimic the actual transcranial light therapy; however, when set to sham the device does not emit skin and cranium penetrating light emitting diode light energy.
Overall Number of Participants Analyzed	18	31
Mean (Standard Deviation); Unit of Measure: score on a scale
	16.28 (5.345)	15.81 (6.685)

4. Secondary Outcome

Title	Hamilton Depression Rating Scale - 17 Items(Phase 2)
Description	assessment of the patient's depressive symptoms, using a structured interview and defined anchor points. The Hamilton Depression Rating Scale aims to quantify the degree of depression in patients who already have a diagnosis of major depression. Score ranges from 0-52. Higher score indicates greater severity of depression.
Time Frame	6 weeks - Sequential-parallel comparison design

Outcome Measure Data

Analysis Population Description

This group consists of all sham participants that did not respond to Sham in Phase 1 and were re-randomized into Phase 2. Therefore, of the 29 participants in Sham, 5 participants were responders, 4 were not re-randomized. 1 participant was not assessed with HAMD but was assessed with primary measure (QIDS), as such there are 10 in TLT group.

Arm/Group Title	Transcranial Light Therapy	Sham Transcranial Light Therapy
Arm/Group Description:	Transcranial light therapy penetrates the skin and brain using light energy and, the light energy may activate under-stimulated brain regions. Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions.	For the sham group, The transcranial light therapy device uses nonpenetrating light emitting diode light energy. The sham controls for which participants improve from the actual transcranial light therapy treatment and which participants improve during the study for reasons other than the therapy Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions. Sham Transcranial Light Therapy: The same device used for the actual transcranial light therapy is used as the sham device; The device, when set to sham, will mimic the actual transcranial light therapy; however, when set to sham the device does not emit skin and cranium penetrating light emitting diode light energy.
Overall Number of Participants Analyzed	10	7
Mean (Standard Deviation); Unit of Measure: score on a scale
	13.50 (6.151)	14.14 (6.768)

Adverse Events

Time Frame	Timeframe of collection was during participation in the two phases of the study and follow up visit 1 week after completion. Therefore, the total timeframe of assessment is 13 weeks.
Adverse Event Reporting Description	Our participants flow differs for the following reasons: Per the SPCD design, subjects within the Sham group in Phase 1 are re-randomized in Phase 2 to receive either Sham or TLT treatment. Therefore, TLT group accounts for participants receiving TLT in the first phase as well as those re-randomized to TLT in their second phase. Participants in Sham account for all subjects randomized to sham in Phase 1, regardless of whether they were re-randomized to Sham or TLT in Phase 2.
Arm/Group Title	Transcranial Light Therapy		Sham Transcranial Light Therapy
Arm/Group Description	Transcranial light therapy penetrates the skin and brain using light energy and, the light energy may activate under-stimulated brain regions. Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions.		For the sham group, The transcranial light therapy device uses nonpenetrating light emitting diode light energy. The sham controls for which participants improve from the actual transcranial light therapy treatment and which participants improve during the study for reasons other than the therapy Transcranial Light Therapy: Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions. Sham Transcranial Light Therapy: The same device used for the actual transcranial light therapy is used as the sham device; The device, when set to sham, will mimic the actual transcranial light therapy; however, when set to sham the device does not emit skin and cranium penetrating light emitting diode light energy.
All-Cause Mortality
	Transcranial Light Therapy		Sham Transcranial Light Therapy
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/31 (0.00%)		0/31 (0.00%)
Serious Adverse Events
	Transcranial Light Therapy		Sham Transcranial Light Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0.00%)		1/31 (3.23%)
Psychiatric disorders
Aborted Suicide Attempt † [1]	0/31 (0.00%)	0	1/31 (3.23%)	1
† Indicates events were collected by systematic assessment; [1] Aborted suicide attempt that triggered a hospitalization while participant was outside of lab.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Transcranial Light Therapy		Sham Transcranial Light Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/31 (38.71%)		17/31 (54.84%)
General disorders
Headache †	9/31 (29.03%)		7/31 (22.58%)
Worsening of Pre-Existing Condition †	3/31 (9.68%)		3/31 (9.68%)
Pressure on Forehead/Head †	4/31 (12.90%)		2/31 (6.45%)
Psychiatric disorders
Insomnia †	5/31 (16.13%)		4/31 (12.90%)
Irritability With and Without Impulsivity †	1/31 (3.23%)		4/31 (12.90%)
Panic Attack †	1/31 (3.23%)		3/31 (9.68%)
Anxiety †	0/31 (0.00%)		2/31 (6.45%)
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Infection †	2/31 (6.45%)		6/31 (19.35%)
† Indicates events were collected by systematic assessment

Limitations and Caveats

For the device utilized in this trial, very low light was applied. In addition, two nodes were obstructed by participants' hair, reducing light delivered.

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.

Results Point of Contact

• Name/Title: Dr. Paolo Cassano
• Organization: Massachusetts General Hospital
• Phone: 617-643-9622
• EMail: pcassano@mgh.harvard.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Iosifescu DV, Norton RJ, Tural U, Mischoulon D, Collins K, McDonald E, De Taboada L, Foster S, Cusin C, Yeung A, Clain A, Schoenfeld D, Hamblin MR, Cassano P. Very Low-Level Transcranial Photobiomodulation for Major Depressive Disorder: The ELATED-3 Multicenter, Randomized, Sham-Controlled Trial. J Clin Psychiatry. 2022 Aug 8;83(5):21m14226. doi: 10.4088/JCP.21m14226.

• Responsible Party: Paolo Cassano, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02959307
• Other Study ID Numbers: 2016P001490
• First Submitted: November 7, 2016
• First Posted: November 9, 2016
• Results First Submitted: June 16, 2020
• Results First Posted: September 21, 2020
• Last Update Posted: September 21, 2020