Trial Outcomes & Findings for Biomarkers in Repetitive Transcranial Magnetic Stimulation (rTMS) for Adolescent Depression (NCT NCT03363919)
NCT ID: NCT03363919
Last Updated: 2024-02-01
Results Overview
CDRS-R is a 17-item scale, with items ranging from 1 to 5 or 1 to 7 (possible total score from 17 to 113), rated by a clinician via interviews with the child and parent. A score of ≥40 is indicative of depression, whereas a score ≤28 is often used to define remission (minimal or no symptoms)
Recruitment status
COMPLETED
Study phase
NA
Target enrollment
47 participants
Primary outcome timeframe
6 weeks
Results posted on
2024-02-01
Participant Flow
Participant milestones
| Measure |
1 Hz Left Prefrontal rTMS
36 sessions of 1 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 continuous pulses.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with Major Depressive Disorder (MDD) who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
10 Hz Left Prefrontal rTMS
36 sessions of 10 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 pulses with 4 seconds on and 36 seconds off.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with Major Depressive Disorder (MDD) who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
|---|---|---|
|
Overall Study
STARTED
|
23
|
24
|
|
Overall Study
COMPLETED
|
22
|
19
|
|
Overall Study
NOT COMPLETED
|
1
|
5
|
Reasons for withdrawal
| Measure |
1 Hz Left Prefrontal rTMS
36 sessions of 1 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 continuous pulses.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with Major Depressive Disorder (MDD) who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
10 Hz Left Prefrontal rTMS
36 sessions of 10 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 pulses with 4 seconds on and 36 seconds off.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with Major Depressive Disorder (MDD) who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
|---|---|---|
|
Overall Study
Withdrawal by subject - did not receive allocated intervention
|
0
|
1
|
|
Overall Study
Withdrawal by subject - discontinued intervention prior to week 1
|
1
|
4
|
Baseline Characteristics
Biomarkers in Repetitive Transcranial Magnetic Stimulation (rTMS) for Adolescent Depression
Baseline characteristics by cohort
| Measure |
1 Hz Left Prefrontal rTMS
n=22 Participants
36 sessions of 1 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 continuous pulses.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with Major Depressive Disorder (MDD) who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
10 Hz Left Prefrontal rTMS
n=19 Participants
36 sessions of 10 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 pulses with 4 seconds on and 36 seconds off.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with Major Depressive Disorder (MDD) who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
Total
n=41 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
15.68 years
STANDARD_DEVIATION 1.83 • n=5 Participants
|
15.89 years
STANDARD_DEVIATION 1.05 • n=7 Participants
|
15.78 years
STANDARD_DEVIATION 1.51 • n=5 Participants
|
|
Sex: Female, Male
Female
|
13 Participants
n=5 Participants
|
12 Participants
n=7 Participants
|
25 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
9 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
16 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
2 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
5 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
20 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
36 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
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
|
1 Participants
n=7 Participants
|
5 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
|
1 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
17 Participants
n=5 Participants
|
17 Participants
n=7 Participants
|
34 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 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
|
|
Region of Enrollment
United States
|
22 participants
n=5 Participants
|
19 participants
n=7 Participants
|
41 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 6 weeksPopulation: Data was not collected or analyzed for one subject in the 1 Hz arm and five subjects in the 10 Hz arm
CDRS-R is a 17-item scale, with items ranging from 1 to 5 or 1 to 7 (possible total score from 17 to 113), rated by a clinician via interviews with the child and parent. A score of ≥40 is indicative of depression, whereas a score ≤28 is often used to define remission (minimal or no symptoms)
Outcome measures
| Measure |
1 Hz Left Prefrontal rTMS
n=22 Participants
36 sessions of 1 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 continuous pulses.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
10 Hz Left Prefrontal rTMS
n=19 Participants
36 sessions of 10 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 pulses with 4 seconds on and 36 seconds off.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
|---|---|---|
|
Total Children's Depression Rating Scale, Revised (CDRS-R) Score
|
41.768 score on a scale
Interval 40.034 to 43.503
|
44.541 score on a scale
Interval 42.633 to 46.448
|
SECONDARY outcome
Timeframe: baseline, 6 weeksPopulation: Data was not collected or analyzed for one subject in the 1 Hz arm and five subjects in the 10 Hz arm
ICF measures were collected with surface electromyography. A subthreshold conditioning stimulus (CS) was set to 80% of resting motor threshold (RMT) preceding a suprathreshold test stimulus (TS), which was calibrated to produce an average motor evoked potential (MEP) of 0.5 to 1.5 millivolt peak-to-peak amplitude in the contralateral abductor pollicis brevis (APB) muscle. Conditioning stimuli were delivered to the motor cortex prior to the TS in 15 msec interstimulus intervals. Changes in TS MEP was expressed as a percentage of the mean unconditioned MEP amplitude.
Outcome measures
| Measure |
1 Hz Left Prefrontal rTMS
n=22 Participants
36 sessions of 1 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 continuous pulses.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
10 Hz Left Prefrontal rTMS
n=19 Participants
36 sessions of 10 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 pulses with 4 seconds on and 36 seconds off.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
|---|---|---|
|
Change in Intracortical Facilitation (ICF)
|
1.71 percentage of the mean unconditioned MEP
Standard Error 0.05
|
1.67 percentage of the mean unconditioned MEP
Standard Error 0.06
|
Adverse Events
1 Hz Left Prefrontal rTMS
Serious events: 3 serious events
Other events: 20 other events
Deaths: 0 deaths
10 Hz Left Prefrontal rTMS
Serious events: 3 serious events
Other events: 21 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
1 Hz Left Prefrontal rTMS
n=23 participants at risk
36 sessions of 1 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 continuous pulses.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
10 Hz Left Prefrontal rTMS
n=24 participants at risk
36 sessions of 10 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 pulses with 4 seconds on and 36 seconds off.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
|---|---|---|
|
Eye disorders
blurred vision
|
4.3%
1/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
0.00%
0/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Psychiatric disorders
suicidal ideation
|
0.00%
0/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
4.2%
1/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Nervous system disorders
severe scalp pain
|
0.00%
0/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
4.2%
1/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Ear and labyrinth disorders
left ear bleeding
|
0.00%
0/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
4.2%
1/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Cardiac disorders
chest pain
|
4.3%
1/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
0.00%
0/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Reproductive system and breast disorders
groin pain
|
4.3%
1/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
0.00%
0/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
Other adverse events
| Measure |
1 Hz Left Prefrontal rTMS
n=23 participants at risk
36 sessions of 1 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 continuous pulses.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
10 Hz Left Prefrontal rTMS
n=24 participants at risk
36 sessions of 10 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 pulses with 4 seconds on and 36 seconds off.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
|
|---|---|---|
|
Psychiatric disorders
Anxiety
|
0.00%
0/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
4.2%
1/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Ear and labyrinth disorders
Auditory
|
13.0%
3/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
16.7%
4/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Nervous system disorders
Dizziness
|
13.0%
3/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
16.7%
4/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Nervous system disorders
Headache
|
47.8%
11/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
50.0%
12/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Psychiatric disorders
Insomnia
|
13.0%
3/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
8.3%
2/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
General disorders
Nausea
|
4.3%
1/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
16.7%
4/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Musculoskeletal and connective tissue disorders
Neck pain
|
0.00%
0/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
4.2%
1/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Psychiatric disorders
Non-Suicidal Self injury
|
4.3%
1/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
0.00%
0/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
General disorders
Pain or Discomfort at Treatment site
|
52.2%
12/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
62.5%
15/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Nervous system disorders
Sedation
|
8.7%
2/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
16.7%
4/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Psychiatric disorders
Suicidal Ideation
|
8.7%
2/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
8.3%
2/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Nervous system disorders
Twitching during treatment
|
4.3%
1/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
20.8%
5/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
|
Psychiatric disorders
Worsening depression
|
4.3%
1/23 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
0.00%
0/24 • Adverse events were collected from baseline (consent signing) to end of study for all participants, approximately 6 weeks.
Adverse events were collected on all participants whether or not they received the intervention.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place