Trial Outcomes & Findings for Efficacy and Safety of Cranial Electrical Stimulation (CES) for Major Depressive Disorder (MDD) (NCT NCT01325532)

Last Updated: 2016-06-01

Results Overview

The Hamilton Depression Rating Scale (HAM-D-17) used here is a 17-item scale that measures severity of depression. Items are individually scored from 0-4 or from 0-2 depending on the item, and the individual scores for each item are added to comprise one score. Higher scores indicate greater severity of depression. Possible scores on the scale range from a minimum of zero (0) to a maximum of 52. This section reports the improvement in depressive symptoms during the course of treatment, i.e. the change in overall score between baseline visit and week 3 visit. Change can occur in either direction (i.e. improvement or worsening). A score of greater than zero indicates a reduction of depressive symptoms (improvement), whereas a score of less than zero indicates an increase in depressive symptoms (worsening).

Recruitment status

COMPLETED

Study phase

Target enrollment

30 participants

Primary outcome timeframe

Baseline-Week 3

Results posted on

2016-06-01

Participant Flow

Subjects were recruited by advertisement from our Depression Clinical and Research Program (DCRP). Informed consent was obtained per IRB guidelines. Investigators who screened subjects were our program's psychiatrists and psychologists, trained and certified in the use of appropriate diagnostic instruments such as the SCID and HAM-D.

Subjects who passed the screen visit returned a week later for the baseline visit. At that time, subjects received their first treatment (or sham) at the site for 20 minutes, including personal instruction of proper technique and electrode placement.

Participant milestones

Participant milestones
Measure	Active CES Active CES: The FW-100 Cranial Stimulator headset was placed on the scalp over the two dorsolateral prefrontal cortex areas. The power knob was turned to maximum setting. The waveform contains a 15000Hz square wave carrier from 0-4 mAmp. The first 15Hz modulating signal provides 50msec of "on" and 16.7msec of "off" time (total 66.7msec, 50% duty cycle). A second 500Hz modulating signal changes the "on" time series of 15000Hz pulses (750 pulses/50msec) into 25 smaller bursts of 15 pulses of the 15000Hz carrier signal, for 375 pulses in 50msec. The consecutive positive burst and "off" time is followed by an opposite negative burst and "off" time, balancing the current component to zero. Output voltage ranges from 0-40V, positive and negative. CES automatically shut off after 20 mins. Active CES: CES current	Sham CES Shame CES: The sham devices were modified to not deliver current to the headset. The current from the active device departs from the posts at the top of the device into the headsets, creating a loop when the headset is worn by the subject with the wet electrode sponges. This loop is eliminated in the sham devices by wrapping wire around the posts, thus containing the loop within the device, with no electricity leaving the headsets. This approach allows the loop to be maintained, and therefore all of the device's green and yellow amperage lights still light up, protecting the blind. Sham CES: Sham CES (device off) for 20-minutes each day 5 days/week for 3 weeks.
Overall Study STARTED	17	13
Overall Study COMPLETED	15	13
Overall Study NOT COMPLETED	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Active CES Active CES: The FW-100 Cranial Stimulator headset was placed on the scalp over the two dorsolateral prefrontal cortex areas. The power knob was turned to maximum setting. The waveform contains a 15000Hz square wave carrier from 0-4 mAmp. The first 15Hz modulating signal provides 50msec of "on" and 16.7msec of "off" time (total 66.7msec, 50% duty cycle). A second 500Hz modulating signal changes the "on" time series of 15000Hz pulses (750 pulses/50msec) into 25 smaller bursts of 15 pulses of the 15000Hz carrier signal, for 375 pulses in 50msec. The consecutive positive burst and "off" time is followed by an opposite negative burst and "off" time, balancing the current component to zero. Output voltage ranges from 0-40V, positive and negative. CES automatically shut off after 20 mins. Active CES: CES current	Sham CES Shame CES: The sham devices were modified to not deliver current to the headset. The current from the active device departs from the posts at the top of the device into the headsets, creating a loop when the headset is worn by the subject with the wet electrode sponges. This loop is eliminated in the sham devices by wrapping wire around the posts, thus containing the loop within the device, with no electricity leaving the headsets. This approach allows the loop to be maintained, and therefore all of the device's green and yellow amperage lights still light up, protecting the blind. Sham CES: Sham CES (device off) for 20-minutes each day 5 days/week for 3 weeks.
Overall Study Withdrawal by Subject	2	0

Baseline Characteristics

Efficacy and Safety of Cranial Electrical Stimulation (CES) for Major Depressive Disorder (MDD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Active CES n=17 Participants Active CES: The FW-100 Cranial Stimulator headset was placed on the scalp over the two dorsolateral prefrontal cortex areas. The power knob was turned to maximum setting. The waveform contains a 15000Hz square wave carrier from 0-4 mAmp. The first 15Hz modulating signal provides 50msec of "on" and 16.7msec of "off" time (total 66.7msec, 50% duty cycle). A second 500Hz modulating signal changes the "on" time series of 15000Hz pulses (750 pulses/50msec) into 25 smaller bursts of 15 pulses of the 15000Hz carrier signal, for 375 pulses in 50msec. The consecutive positive burst and "off" time is followed by an opposite negative burst and "off" time, balancing the current component to zero. Output voltage ranges from 0-40V, positive and negative. CES automatically shut off after 20 mins. Active CES: CES current	Sham CES n=13 Participants Shame CES: The sham devices were modified to not deliver current to the headset. The current from the active device departs from the posts at the top of the device into the headsets, creating a loop when the headset is worn by the subject with the wet electrode sponges. This loop is eliminated in the sham devices by wrapping wire around the posts, thus containing the loop within the device, with no electricity leaving the headsets. This approach allows the loop to be maintained, and therefore all of the device's green and yellow amperage lights still light up, protecting the blind. Sham CES: Sham CES (device off) for 20-minutes each day 5 days/week for 3 weeks.	Total n=30 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	17 Participants n=5 Participants	13 Participants n=7 Participants	30 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	45.5 years STANDARD_DEVIATION 12.3 • n=5 Participants	51.4 years STANDARD_DEVIATION 11.9 • n=7 Participants	48.1 years STANDARD_DEVIATION 12.3 • n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Region of Enrollment United States	17 participants n=5 Participants	13 participants n=7 Participants	30 participants n=5 Participants
Hamilton Depression Rating Scale	18.1 units on a scale STANDARD_DEVIATION 1.5 • n=5 Participants	18.7 units on a scale STANDARD_DEVIATION 3.9 • n=7 Participants	18.3 units on a scale STANDARD_DEVIATION 2.8 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline-Week 3

Population: Intent to treat sample with last observation carried forward for all randomized subject.

Outcome measures

Outcome measures
Measure	Active CES n=17 Participants Active CES: The FW-100 Cranial Stimulator headset was placed on the scalp over the two dorsolateral prefrontal cortex areas. The power knob was turned to maximum setting. The waveform contains a 15000Hz square wave carrier from 0-4 mAmp. The first 15Hz modulating signal provides 50msec of "on" and 16.7msec of "off" time (total 66.7msec, 50% duty cycle). A second 500Hz modulating signal changes the "on" time series of 15000Hz pulses (750 pulses/50msec) into 25 smaller bursts of 15 pulses of the 15000Hz carrier signal, for 375 pulses in 50msec. The consecutive positive burst and "off" time is followed by an opposite negative burst and "off" time, balancing the current component to zero. Output voltage ranges from 0-40V, positive and negative. CES automatically shut off after 20 mins. Active CES: CES current	Sham CES n=13 Participants Shame CES: The sham devices were modified to not deliver current to the headset. The current from the active device departs from the posts at the top of the device into the headsets, creating a loop when the headset is worn by the subject with the wet electrode sponges. This loop is eliminated in the sham devices by wrapping wire around the posts, thus containing the loop within the device, with no electricity leaving the headsets. This approach allows the loop to be maintained, and therefore all of the device's green and yellow amperage lights still light up, protecting the blind. Sham CES: Sham CES (device off) for 20-minutes each day 5 days/week for 3 weeks.
Change in Hamilton Depression Rating Scale (HAM-D 17) Score From Baseline to Week 3	14.8 units on a scale Standard Deviation 6.3	13.6 units on a scale Standard Deviation 5.8

PRIMARY outcome

Timeframe: Baseline-Week 3

Population: Intent to treat sample with all subjects randomized.

This measures the emergence of different adverse (side) effects from treatment during the study. This section will describe the most commonly reported adverse effects. The section on adverse events will describe and detail the full range of AEs reported.

Outcome measures

Outcome measures
Measure	Active CES n=17 Participants Active CES: The FW-100 Cranial Stimulator headset was placed on the scalp over the two dorsolateral prefrontal cortex areas. The power knob was turned to maximum setting. The waveform contains a 15000Hz square wave carrier from 0-4 mAmp. The first 15Hz modulating signal provides 50msec of "on" and 16.7msec of "off" time (total 66.7msec, 50% duty cycle). A second 500Hz modulating signal changes the "on" time series of 15000Hz pulses (750 pulses/50msec) into 25 smaller bursts of 15 pulses of the 15000Hz carrier signal, for 375 pulses in 50msec. The consecutive positive burst and "off" time is followed by an opposite negative burst and "off" time, balancing the current component to zero. Output voltage ranges from 0-40V, positive and negative. CES automatically shut off after 20 mins. Active CES: CES current	Sham CES n=13 Participants Shame CES: The sham devices were modified to not deliver current to the headset. The current from the active device departs from the posts at the top of the device into the headsets, creating a loop when the headset is worn by the subject with the wet electrode sponges. This loop is eliminated in the sham devices by wrapping wire around the posts, thus containing the loop within the device, with no electricity leaving the headsets. This approach allows the loop to be maintained, and therefore all of the device's green and yellow amperage lights still light up, protecting the blind. Sham CES: Sham CES (device off) for 20-minutes each day 5 days/week for 3 weeks.
Reported Side Effects Based on PRISE AE Scores Poor concentration	10 number of subjects reporting	2 number of subjects reporting
Reported Side Effects Based on PRISE AE Scores Decreased energy	6 number of subjects reporting	2 number of subjects reporting
Reported Side Effects Based on PRISE AE Scores Fatigue	5 number of subjects reporting	2 number of subjects reporting
Reported Side Effects Based on PRISE AE Scores Anxiety	5 number of subjects reporting	4 number of subjects reporting
Reported Side Effects Based on PRISE AE Scores Flashing light/tingling	5 number of subjects reporting	0 number of subjects reporting

SECONDARY outcome

Timeframe: Baseline-Week 3

Population: This is an intent to treat (ITT) analysis of all patients randomized.

The Pittsburgh Sleep Quality Index (PSQI) is a patient-rated instrument to assess sleep quality and quantity and its changes throughout the study. Scoring is based on 7 individual components. Each component is scored from 0-3. Higher scores indicate worse sleep. Total global sleep score ranges from zero (0) to 21. We report here the overall change in global sleep score for each treatment arm, i.e. the change in overall score between baseline visit and week 3 visit. Change can occur in either direction (i.e. improvement or worsening). A score of greater than zero indicates a reduction of sleep disturbance (improvement), whereas a score of less than zero indicates an increase in sleep disturbance (worsening).

Outcome measures

Outcome measures
Measure	Active CES n=17 Participants Active CES: The FW-100 Cranial Stimulator headset was placed on the scalp over the two dorsolateral prefrontal cortex areas. The power knob was turned to maximum setting. The waveform contains a 15000Hz square wave carrier from 0-4 mAmp. The first 15Hz modulating signal provides 50msec of "on" and 16.7msec of "off" time (total 66.7msec, 50% duty cycle). A second 500Hz modulating signal changes the "on" time series of 15000Hz pulses (750 pulses/50msec) into 25 smaller bursts of 15 pulses of the 15000Hz carrier signal, for 375 pulses in 50msec. The consecutive positive burst and "off" time is followed by an opposite negative burst and "off" time, balancing the current component to zero. Output voltage ranges from 0-40V, positive and negative. CES automatically shut off after 20 mins. Active CES: CES current	Sham CES n=13 Participants Shame CES: The sham devices were modified to not deliver current to the headset. The current from the active device departs from the posts at the top of the device into the headsets, creating a loop when the headset is worn by the subject with the wet electrode sponges. This loop is eliminated in the sham devices by wrapping wire around the posts, thus containing the loop within the device, with no electricity leaving the headsets. This approach allows the loop to be maintained, and therefore all of the device's green and yellow amperage lights still light up, protecting the blind. Sham CES: Sham CES (device off) for 20-minutes each day 5 days/week for 3 weeks.
Change in Global Sleep Scores on the Pittsburgh Sleep Quality Index (PSQI) From Baseline to Week 3.	0.33 units on a scale Standard Deviation 2.02	0.77 units on a scale Standard Deviation 2.17

Adverse Events

Active CES

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Sham CES

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr David Mischoulon

Massachusetts General Hospital, Dept of Psychiatry

Phone: 617-724-5198

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Active CES n=17 participants at risk Active CES: The FW-100 Cranial Stimulator headset was placed on the scalp over the two dorsolateral prefrontal cortex areas. The power knob was turned to maximum setting. The waveform contains a 15000Hz square wave carrier from 0-4 mAmp. The first 15Hz modulating signal provides 50msec of "on" and 16.7msec of "off" time (total 66.7msec, 50% duty cycle). A second 500Hz modulating signal changes the "on" time series of 15000Hz pulses (750 pulses/50msec) into 25 smaller bursts of 15 pulses of the 15000Hz carrier signal, for 375 pulses in 50msec. The consecutive positive burst and "off" time is followed by an opposite negative burst and "off" time, balancing the current component to zero. Output voltage ranges from 0-40V, positive and negative. CES automatically shut off after 20 mins. Active CES: CES current	Sham CES n=13 participants at risk Shame CES: The sham devices were modified to not deliver current to the headset. The current from the active device departs from the posts at the top of the device into the headsets, creating a loop when the headset is worn by the subject with the wet electrode sponges. This loop is eliminated in the sham devices by wrapping wire around the posts, thus containing the loop within the device, with no electricity leaving the headsets. This approach allows the loop to be maintained, and therefore all of the device's green and yellow amperage lights still light up, protecting the blind. Sham CES: Sham CES (device off) for 20-minutes each day 5 days/week for 3 weeks.
Gastrointestinal disorders Diarrhea	11.8% 2/17 • Number of events 2 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Gastrointestinal disorders Constipation	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	7.7% 1/13 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Gastrointestinal disorders Nausea/vomiting	0.00% 0/17 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	7.7% 1/13 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Cardiac disorders Palpitations	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	7.7% 1/13 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Cardiac disorders Orthostatic hypotension	11.8% 2/17 • Number of events 2 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Skin and subcutaneous tissue disorders Increased perspiration	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Nervous system disorders Headache	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	7.7% 1/13 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Nervous system disorders Tremors	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Nervous system disorders Dizziness	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Eye disorders Blurred vision	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Ear and labyrinth disorders Ringing in ears	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	7.7% 1/13 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Renal and urinary disorders Difficulty urinating	0.00% 0/17 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	7.7% 1/13 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Renal and urinary disorders Frequent urination	0.00% 0/17 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	7.7% 1/13 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Reproductive system and breast disorders Menstrual irregularity	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
General disorders Difficulty sleeping	17.6% 3/17 • Number of events 3 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	15.4% 2/13 • Number of events 2 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
General disorders Sleeping too much	17.6% 3/17 • Number of events 3 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	7.7% 1/13 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Reproductive system and breast disorders Loss of sexual desire	17.6% 3/17 • Number of events 3 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	7.7% 1/13 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Reproductive system and breast disorders Trouble achieving orgasm	11.8% 2/17 • Number of events 2 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Reproductive system and breast disorders Trouble with erections	5.9% 1/17 • Number of events 1 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Psychiatric disorders Anxiety	29.4% 5/17 • Number of events 5 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	30.8% 4/13 • Number of events 4 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Psychiatric disorders Poor concentration	58.8% 10/17 • Number of events 10 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	15.4% 2/13 • Number of events 2 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Psychiatric disorders General malaise	29.4% 5/17 • Number of events 5 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Psychiatric disorders Restlessness	17.6% 3/17 • Number of events 3 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	15.4% 2/13 • Number of events 2 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Psychiatric disorders Fatigue	29.4% 5/17 • Number of events 5 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	15.4% 2/13 • Number of events 2 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Psychiatric disorders Decreased energy	35.3% 6/17 • Number of events 6 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	15.4% 2/13 • Number of events 2 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.
Nervous system disorders Flashing light and tingling sensation	29.4% 5/17 • Number of events 5 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.	0.00% 0/13 • 3 weeks All subjects filled out the PRISE adverse effect instrument at each visit. Emergence of each side effect was assessed during the course of the study.