Cognitive Dysfunction in Parkinson's Disease

• ClinicalTrials.gov Identifier: NCT02346708
• Recruitment Status: Active, not recruiting
• First Posted: January 27, 2015
• Results First Posted: December 9, 2020
• Last Update Posted: December 9, 2020
• Sponsor: University of Colorado, Denver
• Collaborators: National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): University of Colorado, Denver

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Parkinson's Disease
• Interventions: Device: Real TMS; Device: Sham TMS
• Enrollment: 49

Participant Flow

Recruitment Details	Recruitment was conducted in the United States at one site: University of Colorado Denver - Anschutz Medical Campus. The first participant was enrolled in May 19, 2014.
Pre-assignment Details	70 participants were assessed for eligibility (following Inclusion and exclusion criteria), 21 were screen failures, 49 participants were randomized to treatment.

Arm/Group Title	Real TMS	Sham TMS
Arm/Group Description	TMS will be administered using a 70-mm diameter air-cooled figure-of-8 coil and SuperRapid2 Magstim Stimulator. Repetitive pulses will be delivered to the right and left dorsolateral pre-frontal cortex (Brodmann area 46) using a frameless stereotactic navigation system and the subject's magnetic resonance imaging (MRI) in Brainsight software. Stimuli will be delivered at 20 Hz at 90% resting motor threshold (rMT) for 25 trains of 30 pulses per train, inter-train interval of 30 seconds for a total of 750 pulses per hemisphere. This dose and duration of repetitive TMS (rTMS) is based on physiological studies of healthy adults and treatment studies of cognition in PD and Alzheimer's disease. Side of first stimulation (left vs right hemisphere) will be counterbalanced across subjects. Real TMS: real treatment	Sham stimulation will be delivered using a sham coil fitted with electrodes to mimic both the auditory and somatic sensation of real TMS. Sham TMS: placebo treatment
Period Title: Overall Study
Started	24	25
Completed	22	24
Not Completed	2	1
Reason Not Completed
Adverse Event	2	0
Protocol Violation	0	1

Baseline Characteristics

Arm/Group Title		Real TMS	Sham TMS	Total
Arm/Group Description		TMS will be administered using a 70-mm diameter air-cooled figure-of-8 coil and SuperRapid2 Magstim Stimulator. Repetitive pulses will be delivered to the right and left dorsolateral pre-frontal cortex (Brodmann area 46) using a frameless stereotactic navigation system and the subject's magnetic resonance imaging (MRI) in Brainsight software. Stimuli will be delivered at 20 Hz at 90% resting motor threshold (rMT) for 25 trains of 30 pulses per train, inter-train interval of 30 seconds for a total of 750 pulses per hemisphere. Stimulation will be delivered for 10 consecutive days, excluding the weekends. This dose and duration of repetitive TMS (rTMS) is based on physiological studies of healthy adults and treatment studies of cognition in PD and Alzheimer's disease. Side of first stimulation (left vs right hemisphere) will be counterbalanced across subjects. Real TMS: real treatment	Sham stimulation will be delivered using a sham coil fitted with electrodes to mimic both the auditory and somatic sensation of real TMS. Sham TMS: placebo treatment	Total of all reporting groups
Overall Number of Baseline Participants		22	24	46
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	24 participants	46 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	8 36.4%	7 29.2%	15 32.6%
	>=65 years	14 63.6%	17 70.8%	31 67.4%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	22 participants	24 participants	46 participants
		67.4 (7.2)	69.5 (8)	68.5 (7.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	24 participants	46 participants
	Female	6 27.3%	7 29.2%	13 28.3%
	Male	16 72.7%	17 70.8%	33 71.7%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	24 participants	46 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	1 4.5%	0 0.0%	1 2.2%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 4.5%	0 0.0%	1 2.2%
	White	20 90.9%	24 100.0%	44 95.7%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	22 participants	24 participants	46 participants
		22	24	46

Outcome Measures

1. Primary Outcome

Title	Change in Magnetoencephalography (MEG) Connectivity Measures
Description	Our MEG outcome will be a change in small-worldness, global efficiency, nodal efficiency and degree distribution pre-TMS to immediately post-TMS treatment.
Time Frame	2 weeks

Outcome Measure Data

Analysis Population Description

No data displayed because Outcome Measure has zero total analyzed. No participants were analyzed for this outcome measure.

Arm/Group Title	Real TMS	Sham TMS
Arm/Group Description:	TMS will be administered using a 70-mm diameter air-cooled figure-of-8 coil and SuperRapid2 Magstim Stimulator. Repetitive pulses will be delivered to the right and left dorsolateral pre-frontal cortex (Brodmann area 46) using a frameless stereotactic navigation system and the subject's magnetic resonance imaging (MRI) in Brainsight software. Stimuli will be delivered at 20 Hz at 90% resting motor threshold (rMT) for 25 trains of 30 pulses per train, inter-train interval of 30 seconds for a total of 750 pulses per hemisphere. This dose and duration of repetitive TMS (rTMS) is based on physiological studies of healthy adults and treatment studies of cognition in PD and Alzheimer's disease.52, 123 Side of first stimulation (left vs right hemisphere) will be counterbalanced across subjects. Real TMS: real treatment	Sham stimulation will be delivered using a sham coil fitted with electrodes to mimic both the auditory and somatic sensation of real TMS. Sham TMS: placebo treatment
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

2. Secondary Outcome

Title	Post-TMS Change From Baseline in Cognitive Scores
Description	Our behavioral outcome will be a change in the scores of the following tests: Mattis Dementia Rating Scale: Higher raw scores = better cognitive status, ranging from 0 to 144. Normative data in healthy subjects range from 137 to 144. Trail Making Test Trails B: average score is 75 seconds; deficient score is > 273 seconds. Delis-Kaplan Executive Function System (DKEFS) - Verbal Fluency Test. Higher score = higher ability in language processing. Scales scores vary from 0 min to N/A max (no concrete maximum). DKEFS - Stroop Interference Test measures inhibitory control and cognitive flexibility. Performance is measured by completion time. No min or max value for this test. Test should be discontinued after 90 sec. For those, higher scores = higher abilities: California Verbal Learning Test (declarative memory, scale 0 to 80), Boston Naming Test (language, scale 0 to 60), Brief Test of Attention and Judgment of Line Orientation (scale 0 to 30)
Time Frame	2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Real TMS	Sham TMS
Arm/Group Description:	TMS will be administered using a 70-mm diameter air-cooled figure-of-8 coil and SuperRapid2 Magstim Stimulator. Repetitive pulses will be delivered to the right and left dorsolateral pre-frontal cortex (Brodmann area 46) using a frameless stereotactic navigation system and the subject's magnetic resonance imaging (MRI) in Brainsight software. Stimuli will be delivered at 20 Hz at 90% resting motor threshold (rMT) for 25 trains of 30 pulses per train, inter-train interval of 30 seconds for a total of 750 pulses per hemisphere. This dose and duration of repetitive TMS (rTMS) is based on physiological studies of healthy adults and treatment studies of cognition in PD and Alzheimer's disease. Side of first stimulation (left vs right hemisphere) will be counterbalanced across subjects. Real TMS: real treatment	Sham stimulation will be delivered using a sham coil fitted with electrodes to mimic both the auditory and somatic sensation of real TMS. Sham TMS: placebo treatment
Overall Number of Participants Analyzed	22	24
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Score on the Mattis Dementia Rating Scale (MDRS) at 2 weeks minus score on the MDRS at baseline	-1.4 (4.55)	0 (5.55)
Score on the Verbal fluency at 2 weeks minus score on the Verbal fluency at baseline	0.3 (11.35)	1 (15.7)
Score on the Stroop Interference at 2 weeks minus score on the Stroop Interference at baseline	-9.1 (18.55)	-2.9 (18.85)
Score on the Brief Test of Attention (BTA) at 2 weeks minus score on the BTA at baseline	-0.1 (4)	0.6 (4.15)
Score on the Boston Naming Test (BNT) at 2 weeks minus score on the BNT at baseline	0.2 (5.95)	1.4 (2.25)
Score on the Judgment of Line Orientation (JLO) at 2 weeks minus score on the JLO at baseline	0.9 (4.7)	1 (4.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Real TMS, Sham TMS
	Comments	We estimated a sample size of 20 per group would provide at least 80% power at a significance level of 0.05 to detect a between-group difference of 10 on the Matthis Dementia Rating Scale-2, an effect size similar to prior studies of rivastigmine.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1
	Comments	We determined whether there was a significant group difference between the real and sham treated PD-MCI patients on the DRS-2 change following rTMS using mixed model regression (MMR) to fit longitudinal models.
	Method	Mixed Models Analysis
	Comments	degrees of freedom: 46
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.07
	Confidence Interval	(2-Sided) 95%; -4.56 to 0.42
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Adverse event data was collected throughout the study, i.e. 6 weeks.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Real TMS		Sham TMS
Arm/Group Description	TMS will be administered using a 70-mm diameter air-cooled figure-of-8 coil and SuperRapid2 Magstim Stimulator. Repetitive pulses will be delivered to the right and dorsolateral left pre-frontal cortex (Brodmann area 46) using a frameless stereotactic navigation system and the subject's magnetic resonance imaging (MRI) in Brainsight software. Stimuli will be delivered at 20 Hz at 90% resting motor threshold (rMT) for 25 trains of 30 pulses per train, inter-train interval of 30 seconds for a total of 750 pulses per hemisphere. This dose and duration of repetitive TMS (rTMS) is based on physiological studies of healthy adults and treatment studies of cognition in PD and Alzheimer's disease. Side of first stimulation (left vs right hemisphere) will be counterbalanced across subjects. Real TMS: real treatment		Sham stimulation will be delivered using a sham coil fitted with electrodes to mimic both the auditory and somatic sensation of real TMS. Sham TMS: placebo treatment
All-Cause Mortality
	Real TMS		Sham TMS
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/22 (0.00%)		0/24 (0.00%)
Serious Adverse Events
	Real TMS		Sham TMS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/22 (4.55%)		0/24 (0.00%)
Renal and urinary disorders
Hospitalization *	1/22 (4.55%)	1	0/24 (0.00%)	0
* Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Real TMS		Sham TMS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/22 (27.27%)		1/24 (4.17%)
Blood and lymphatic system disorders
vasovagal syncope *	1/22 (4.55%)	1	0/24 (0.00%)	0
Eye disorders
mild blurry vision *	1/22 (4.55%)	1	0/24 (0.00%)	0
Infections and infestations
mild flu *	1/22 (4.55%)	1	0/24 (0.00%)	0
Nervous system disorders
motor problems *	0/22 (0.00%)	0	1/24 (4.17%)	1
confusion *	0/22 (0.00%)	0	1/24 (4.17%)	1
Psychiatric disorders
hallucinations *	1/22 (4.55%)	1	0/24 (0.00%)	0
Skin and subcutaneous tissue disorders
local pain *	1/22 (4.55%)	1	0/24 (0.00%)	0
Vascular disorders
burst vein in eye *	1/22 (4.55%)	1	0/24 (0.00%)	0
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

Our specialized MEG data analyst working on the Primary outcome has encountered a Covid-related family emergency, which has delayed the analysis process.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Isabelle Buard, PhD
• Organization: University of Colorado Denver - Anschutz Medical Campus
• Phone: (303)724-5973
• EMail: Isabelle.Buard@cuanschutz.edu

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT02346708
• Other Study ID Numbers: 13-2724; 1K02NS080885-01A1 ( U.S. NIH Grant/Contract )
• First Submitted: January 9, 2015
• First Posted: January 27, 2015
• Results First Submitted: April 6, 2020
• Results First Posted: December 9, 2020
• Last Update Posted: December 9, 2020