Trial Outcomes & Findings for Mindful Breathing and tDCS for Depression (NCT NCT03897699)

Last Updated: 2023-01-13

Results Overview

Change in dorsolateral prefrontal cortex connectivity with the salience network and the default mode using functional MRI compared between treatment groups: Right Amygdala and left DLPFC. Lower connectivity may represent a reduced tendency to engage in maladaptive, repetitive negative thinking. For r-values, 0 represents that the timeseries of the respective ROIs are not correlated. A better outcome may be indexed by lower connectivity (e.g., negative R values), which may represent a greater ability of the DLPFC to downregulate the amygdala and, which in turn may reduce the tendency to engage in maladaptive, repetitive negative thinking.

Recruitment status

COMPLETED

Study phase

Target enrollment

68 participants

Primary outcome timeframe

Baseline and 5 week

Results posted on

2023-01-13

Participant Flow

Participant milestones

Participant milestones
Measure	Active tDCS + Mindful Breathing Training 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Overall Study STARTED	21	22
Overall Study COMPLETED	16	20
Overall Study NOT COMPLETED	5	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Mindful Breathing and tDCS for Depression

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Active tDCS + Mindful Breathing Training n=16 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=20 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.	Total n=36 Participants Total of all reporting groups
Age, Continuous	21.2 years STANDARD_DEVIATION 2.42 • n=5 Participants	20.5 years STANDARD_DEVIATION 2.26 • n=7 Participants	20.9 years STANDARD_DEVIATION 2.19 • n=5 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	20 Participants n=7 Participants	36 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	11 Participants n=5 Participants	16 Participants n=7 Participants	27 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 5 week

Outcome measures

Outcome measures
Measure	Active tDCS + Mindful Breathing Training n=15 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=15 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Change in DLPFC Connectivity: Amygdala	0.0977 r-value Standard Deviation 0.123	-0.057 r-value Standard Deviation 0.133

PRIMARY outcome

Timeframe: 5 weeks from baseline

Change in dorsolateral prefrontal cortex connectivity with the salience network and the default mode using functional MRI compared between treatment groups: default mode network and left DLPFC. Lower DLPFC and DMN connectivity may represent adaptive switching between thinking states to focus on a task at hand or to engage in more reflective, introspective thinking patterns. For r-values, 0 represents that the timeseries of the respective ROIs are not correlated. Change in dorsolateral prefrontal cortex connectivity with the salience network and the default mode using functional MRI compared between treatment groups: default mode network and left DLPFC. A better outcome may be indexed by lower DLPFC and DMN connectivity (e.g., negative R values), which may represent adaptive switching between thinking states to focus on a task at hand or to engage in more reflective, introspective thinking patterns.

Outcome measures

Outcome measures
Measure	Active tDCS + Mindful Breathing Training n=15 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=15 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Change in DLPFC Connectivity: DMN	0.0582 r-value Standard Deviation 0.139	-0.00604 r-value Standard Deviation 0.106

SECONDARY outcome

Timeframe: Baseline and 5 weeks

Montgomery-Åsberg Depression Rating Scale - self-assessment (MADRS-S) measures change in severity of depression symptoms over time. Treatment response will be measured using the MADRS-S and a \~50% reduction in depression severity, i.e. total MADRS-S score, will indicate a positive response to treatment. The scale includes 9 items that are rated by participants on a 4-point Likert scale ranging from 0 - 3. Half-point scores are also possible, i.e 0.5, 1.5, 2.5. Participants rate their symptoms from over the past 3 days and the range of total possible scores is 0 - 27, with a higher score indicating greater severity of symptoms. Bondolfi et al. (2010) found good internal consistency for the MADRS-S, as well as good concurrent validity between the MADRS (clinician administered) and the MADRS-S. Lastly, the MADRS-S was found to be sensitive to change in depression symptoms over time.

Outcome measures

Outcome measures
Measure	Active tDCS + Mindful Breathing Training n=16 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=20 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Change in Depression MADRS-S	6.47 units on a scale Standard Deviation 4.69	5.95 units on a scale Standard Deviation 4.04

SECONDARY outcome

Timeframe: Baseline and 9 weeks

Mindful Attention and Awareness Scale (MAAS) measures presence or absence of awareness of what is happening in the present. The MAAS consists of 15 items. Participants are requested to rate each item according to a 6-point Likert scale with the following options: "Almost Always", "Very Frequently", "Somewhat Frequently", "Somewhat Infrequently", "Very Infrequently", and "Almost Never". Previous study reported that the MAAS was internally consistent and a reliable measure. MAAS score ranges from 1 to 6, with a higher score indicating a greater awareness of inner experiences and mindfulness. In the present study, an increase in the total MAAS score would indicate an increase in presence of awareness of what is happening in the present.

Outcome measures

Outcome measures
Measure	Active tDCS + Mindful Breathing Training n=16 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=20 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Change in Mindfulness MAAS	0.929 units on a scale Standard Deviation 0.992	0.352 units on a scale Standard Deviation 0.859

SECONDARY outcome

Timeframe: Baseline and 9 weeks

Ruminative Response Scale (RRS) measures rumination, which refers to thoughts and behaviors centered around one's symptoms and their causes, as well as potential consequences. Nolen-Hoeksema, Morrow, \& Fredrickson (1993) reported that ruminative thoughts correlated with depressed mood. They further reported a consistency in ruminative responses over a 30-day period. The RRS will be used to measure changes in rumination in the present study. The measure consists of a total of 22 statements that describe ruminative thoughts and participants are requested to rate each statement on a scale of 1 - 4, 1 being "Almost Never" and 4 being "Almost Always". Change in rumination corresponds with a change in the total RRS score. Total scores range from 22 to 88.

Outcome measures

Outcome measures
Measure	Active tDCS + Mindful Breathing Training n=16 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=20 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Change in Rumination RRS	13.9 units on a scale Standard Deviation 16.6	16.1 units on a scale Standard Deviation 12.7

SECONDARY outcome

Timeframe: Baseline and 9 weeks

Freiburg Mindfulness Inventory (FMI) assesses curious attitude toward the mindfulness experience. The FMI contains 14 statements related to mindfulness experiences. Participants are requested to rate each statement according to a 4-point Likert scale ranging from "Rarely" to "Almost Always". An increase in the FMI total score would indicate an increase in mindfulness. Walach et al. (2006) reported that the FMI is a valid and reliable measure of mindfulness. Total scores range from 14 to 56.

Outcome measures

Outcome measures
Measure	Active tDCS + Mindful Breathing Training n=16 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=20 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Change in Mindfulness FMI	9.07 number on a scale Standard Deviation 8.3	6.72 number on a scale Standard Deviation 7.4

SECONDARY outcome

Timeframe: 9 weeks

Measure of occurrence of negative side-effects from treatment. Side effects will be collected via participant self-report. Number of serious and non-serious adverse events will be considered in determining safety of the treatment. A higher number of adverse events will indicate lower treatment safety.

Outcome measures

Outcome measures
Measure	Active tDCS + Mindful Breathing Training n=21 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=22 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Safety: Serious and Non-Serious Adverse Events	486 adverse events	654 adverse events

SECONDARY outcome

Timeframe: 9 weeks

Number of participants enrolled. A high number of participants enrolled will indicate a higher level of tolerability of the treatment.

Outcome measures

Outcome measures
Measure	Active tDCS + Mindful Breathing Training n=21 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=22 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Tolerability: Enrollment and Drop-Out	21 participants	22 participants

SECONDARY outcome

Timeframe: 9 weeks

Number of participants who drop-out due to inability to tolerate treatment. A high number of participant drop-outs will indicate a lower level of tolerability of the treatment.

Outcome measures

Outcome measures
Measure	Active tDCS + Mindful Breathing Training n=21 Participants 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=22 Participants The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Tolerability: Drop-Out	0 Participants	1 Participants

Adverse Events

Active tDCS + Mindful Breathing Training

Serious events: 0 serious events

Other events: 21 other events

Deaths: 0 deaths

Sham tDCS + Mindful Breathing Training

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Kathryn Cullen

University of Minnesota

Phone: 612-273-9732

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Active tDCS + Mindful Breathing Training n=21 participants at risk 20 minutes of active or sham stimulation will be applied at 2.0 mA in parallel with mindful breathing training Transcranial Direct Current Stimulation: A non-invasive neuromodulation technique that can modulate neural activity. Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web.	Sham tDCS + Mindful Breathing Training n=22 participants at risk The sham condition will apply stimulation only for the first and last 30 seconds of the 20-minute session Mindful Breathing: MBT is a mindfulness-based intervention that guides participants to pay attention to the present experience. Participants will be trained to become aware of mind-wandering, disengage, and shift attention back to the present experience. Participants will practice mindful breathing using a computerized application that they will be able to access on the web. Sham: Weak electrical current (\~2mA) is applied to the scalp using anodal and cathodal electrode sponges, which increase or decrease cortical excitability respectively. Sham stimulation will serve as a control condition with current applied only for the first and last 30 seconds of the 20-minute session.
Musculoskeletal and connective tissue disorders Neck pain	33.3% 7/21 • Number of events 22 • Adverse event data were collected over a 9 week period per participant starting at baseline.	45.5% 10/22 • Number of events 22 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders Headache	47.6% 10/21 • Number of events 21 • Adverse event data were collected over a 9 week period per participant starting at baseline.	68.2% 15/22 • Number of events 30 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders unusual feelings on skin of head	52.4% 11/21 • Number of events 42 • Adverse event data were collected over a 9 week period per participant starting at baseline.	77.3% 17/22 • Number of events 88 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders tingling	47.6% 10/21 • Number of events 58 • Adverse event data were collected over a 9 week period per participant starting at baseline.	81.8% 18/22 • Number of events 101 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders itchiness	66.7% 14/21 • Number of events 85 • Adverse event data were collected over a 9 week period per participant starting at baseline.	95.5% 21/22 • Number of events 152 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders sleepliness	71.4% 15/21 • Number of events 101 • Adverse event data were collected over a 9 week period per participant starting at baseline.	86.4% 19/22 • Number of events 79 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders difficulty paying attention	52.4% 11/21 • Number of events 40 • Adverse event data were collected over a 9 week period per participant starting at baseline.	40.9% 9/22 • Number of events 36 • Adverse event data were collected over a 9 week period per participant starting at baseline.
Psychiatric disorders unusual feelings, attitude, emotions	9.5% 2/21 • Number of events 2 • Adverse event data were collected over a 9 week period per participant starting at baseline.	13.6% 3/22 • Number of events 4 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders tooth pain	4.8% 1/21 • Number of events 1 • Adverse event data were collected over a 9 week period per participant starting at baseline.	13.6% 3/22 • Number of events 3 • Adverse event data were collected over a 9 week period per participant starting at baseline.
Ear and labyrinth disorders change in hearing	0.00% 0/21 • Adverse event data were collected over a 9 week period per participant starting at baseline.	9.1% 2/22 • Number of events 2 • Adverse event data were collected over a 9 week period per participant starting at baseline.
Gastrointestinal disorders nausea	14.3% 3/21 • Number of events 5 • Adverse event data were collected over a 9 week period per participant starting at baseline.	18.2% 4/22 • Number of events 8 • Adverse event data were collected over a 9 week period per participant starting at baseline.
Musculoskeletal and connective tissue disorders twitches	19.0% 4/21 • Number of events 9 • Adverse event data were collected over a 9 week period per participant starting at baseline.	40.9% 9/22 • Number of events 24 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders Dizziness	14.3% 3/21 • Number of events 4 • Adverse event data were collected over a 9 week period per participant starting at baseline.	27.3% 6/22 • Number of events 9 • Adverse event data were collected over a 9 week period per participant starting at baseline.
Psychiatric disorders anxiety/worry/nervousness	47.6% 10/21 • Number of events 44 • Adverse event data were collected over a 9 week period per participant starting at baseline.	54.5% 12/22 • Number of events 55 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders forgetfulness	33.3% 7/21 • Number of events 17 • Adverse event data were collected over a 9 week period per participant starting at baseline.	13.6% 3/22 • Number of events 15 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders balance issue	0.00% 0/21 • Adverse event data were collected over a 9 week period per participant starting at baseline.	9.1% 2/22 • Number of events 2 • Adverse event data were collected over a 9 week period per participant starting at baseline.
Musculoskeletal and connective tissue disorders hand movement change	4.8% 1/21 • Number of events 1 • Adverse event data were collected over a 9 week period per participant starting at baseline.	0.00% 0/22 • Adverse event data were collected over a 9 week period per participant starting at baseline.
General disorders abnormal sleep	52.4% 11/21 • Number of events 32 • Adverse event data were collected over a 9 week period per participant starting at baseline.	40.9% 9/22 • Number of events 24 • Adverse event data were collected over a 9 week period per participant starting at baseline.
Musculoskeletal and connective tissue disorders muscle knot/ right shoulder stiffness	4.8% 1/21 • Number of events 1 • Adverse event data were collected over a 9 week period per participant starting at baseline.	0.00% 0/22 • Adverse event data were collected over a 9 week period per participant starting at baseline.
Injury, poisoning and procedural complications Bike accident	4.8% 1/21 • Number of events 1 • Adverse event data were collected over a 9 week period per participant starting at baseline.	0.00% 0/22 • Adverse event data were collected over a 9 week period per participant starting at baseline.