Phase II Subthalamic Nucleus (STN) vs. Globus Pallidus (GPi) Trial

• ClinicalTrials.gov Identifier: NCT01076452
• Recruitment Status: Completed
• First Posted: February 26, 2010
• Results First Posted: January 15, 2014
• Last Update Posted: July 14, 2014
• Sponsor: US Department of Veterans Affairs
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Medtronic
• Information provided by (Responsible Party): VA Office of Research and Development ( US Department of Veterans Affairs )

Tracking Information

• First Submitted Date: February 24, 2010
• First Posted Date: February 26, 2010
• Results First Submitted Date: September 11, 2013
• Results First Posted Date: January 15, 2014
• Last Update Posted Date: July 14, 2014
• Study Start Date: April 2002
• Actual Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 26, 2013)

The Change From Baseline in the UPDRS-III Score at 24 Months With Deep-brain Stimulation and Without Medication. [ Time Frame: Baseline and 24 months ]

The primary outcome measure for the comparison of GPi deep brain stimulation (DBS) to STN DBS is the motor function score of the Unified Parkinson's Disease Rating Scale (UPDRS Part III) measured while the patient is off medications and on stimulation at follow-up visits post surgery. UPDRS Part III has 14 items assessing motor skills including facial expression and speech, tremors, rigidity, posture, gait, and bradykinesia. Left and right sides (arms, legs, and hands) are assessed separately for seven of the functions. The motor function (UPDRS part III) assessments are done by turning on the stimulation with and without taking PD medications (on/off) at each in-person visit. A summary score ranging from 0 to 108 is generated by adding the 14 specific motor function responses. The higher score indicates the worse motor function.

• Original Primary Outcome Measures (submitted: February 25, 2010): Blinded assessment of motor function (Unified Parkinson's Disease Rating Scale (UPDRS) Part III) scores in the on stimulation/off medication condition [ Time Frame: at two years ]

Current Secondary Outcome Measures (submitted: November 26, 2013)

• The Change From Baseline in the UPDRS Scores Part I (Mentation) at 24 Months. [ Time Frame: Baseline and 24 months ]
  The UPDRS has four parts (Parts I-IV) in which a total of 42 disease characteristics are assessed. Most characteristics are assessed according to their severity on a 0-4 scale (0 = normal, 4 = most substantial impairment), and some are assessed only for absence (score = 0) or presence (score = 1). Part I has four items assessing intellectual impairment, thought disorder, depression and motivation. A summary score ranging from 0 to16 is generated by adding the four items. The higher score indicates worse condition.
• The Change From Baseline in the UPDRS Scores Part II (Activity of Daily Living) at 24 Months. [ Time Frame: Baseline and 24 months ]
  The UPDRS has four parts (Parts I-IV) in which a total of 42 disease characteristics are assessed. Most characteristics are assessed according to their severity on a 0-4 scale (0 = normal, 4 = most substantial impairment), and some are assessed only for absence (score = 0) or presence (score = 1). Part II has 13 items focusing on activities of daily living including walking, writing, dressing and speech. A summary score ranging from 0 to 52 is generated by adding the 13 items. The higher score indicates worse condition.
• The Change From Baseline in the UPDRS Scores Part IV (Complication of Therapy) at 24 Months. [ Time Frame: Baseline and 24 months ]
  The UPDRS has four parts (Parts I-IV) in which a total of 42 disease characteristics are assessed. Most characteristics are assessed according to their severity on a 0-4 scale (0 = normal, 4 = most substantial impairment), and some are assessed only for absence (score = 0) or presence (score = 1). Part IV includes four categories (11 items) related to dyskinesias, clinical fluctuations of symptoms, and other complications. A summary score ranging from 0 to 23 is generated by adding the four items. The higher score indicates worse condition.

Original Secondary Outcome Measures (submitted: February 25, 2010)

• Self-reported function [ Time Frame: at two years ]
• UPDRS scores [ Time Frame: at two years ]
• Quality of life [ Time Frame: at two years ]
• Neurocognitive function [ Time Frame: at two years ]
• Adverse events [ Time Frame: at two years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase II Subthalamic Nucleus (STN) vs. Globus Pallidus (GPi) Trial
• Official Title: CSP #468 Phase II - A Comparison of Best Medical Therapy and Deep Brain Stimulation of Subthalamic Nucleus and Globus Pallidus for the Treatment of Parkinson's Disease, Phase II
• Brief Summary: The goal of the second phase of the study is to determine if simultaneous bilateral subthalamic nucleus stimulation or simultaneous bilateral globus pallidus stimulation is more effective in reducing symptoms of Parkinson's Disease.
• Detailed Description: Deep Brain Stimulation (DBS) is a promising therapy for Parkinson's disease (PD) Whether DBS is superior to comprehensive best medical therapy or whether some patients or symptoms respond better to DBS in one area of the brain or the other is currently not known. The goals of this project are to compare the effectiveness of DBS and comprehensive medical therapy as treatments for PD (Phase I) and to compare bilateral DBS at 2 areas of the brain-the subthalamic nucleus (STN) and the globus pallidus (GPi) -to determine the most effective brain site for surgical intervention (Phase II) In this prospective, randomized, multi-center trial, 316 patients will be enrolled at 13 centers over four and a half years. Patients will initially be randomized to immediate surgery (DBS) or to 6 months of "best medical therapy". BMT arm patients will then be randomized to proceed into the DBS surgical phase of the trial. The DBS site (STN pr GPi) will be assigned on a random basis at the time the patient enters the surgical phase of the trial. Patients will be followed for two years post surgery (24 months for DBS only patients and 30 months for BMT-DBS patients) Effective 8/5/05 randomization to the BMT arm has been discontinued since the study has sufficient information to compare the outcomes of DBS and BMT patients at 6 months. The findings will be critically important in establishing the optimal surgical treatment of the disabling symptoms of PD.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: Parkinson's Disease

Intervention

Device: Bilateral Deep Brain Stimulation

The DBS site (STN or GPi) was assigned on a random basis at the time the patient enters the surgical phase of the trial.

Study Arms

• Active Comparator: STN
  Participants were randomized to receive deep brain stimulation on STN (Subthalamic Nucleus) target.
  Intervention: Device: Bilateral Deep Brain Stimulation
• Active Comparator: GPi
  Participants were randomized to receive deep brain stimulation on GPi (Globus Pallidus) target.
  Intervention: Device: Bilateral Deep Brain Stimulation

Publications *

• Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr, Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein J, Stoner G, Heemskerk J, Huang GD; CSP 468 Study Group. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009 Jan 7;301(1):63-73. doi: 10.1001/jama.2008.929.
• Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, Marks WJ Jr, Rothlind J, Sagher O, Moy C, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein JM, Stoner G, Starr PA, Simpson R, Baltuch G, De Salles A, Huang GD, Reda DJ; CSP 468 Study Group. Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease. N Engl J Med. 2010 Jun 3;362(22):2077-91. doi: 10.1056/NEJMoa0907083.
• Weaver FM, Follett KA, Stern M, Luo P, Harris CL, Hur K, Marks WJ Jr, Rothlind J, Sagher O, Moy C, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein JM, Stoner G, Starr PA, Simpson R, Baltuch G, De Salles A, Huang GD, Reda DJ; CSP 468 Study Group. Randomized trial of deep brain stimulation for Parkinson disease: thirty-six-month outcomes. Neurology. 2012 Jul 3;79(1):55-65. doi: 10.1212/WNL.0b013e31825dcdc1. Epub 2012 Jun 20.
• Weintraub D, Duda JE, Carlson K, Luo P, Sagher O, Stern M, Follett KA, Reda D, Weaver FM; CSP 468 Study Group. Suicide ideation and behaviours after STN and GPi DBS surgery for Parkinson's disease: results from a randomised, controlled trial. J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1113-8. doi: 10.1136/jnnp-2012-304396. Epub 2013 May 10.
• Rothlind JC, York MK, Carlson K, Luo P, Marks WJ Jr, Weaver FM, Stern M, Follett K, Reda D; CSP-468 Study Group. Neuropsychological changes following deep brain stimulation surgery for Parkinson's disease: comparisons of treatment at pallidal and subthalamic targets versus best medical therapy. J Neurol Neurosurg Psychiatry. 2015 Jun;86(6):622-9. doi: 10.1136/jnnp-2014-308119. Epub 2014 Sep 2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 7, 2013): 299
• Original Actual Enrollment (submitted: February 25, 2010): 316
• Actual Study Completion Date: April 2009
• Actual Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• idiopathic Parkinson's Disease
• Hoehn and Yahr stage 2 or worse when off medications
• L-dopa responsive with clearly defined "on" periods (i.e. symptoms improve at least partially with L-dopa administration, a characteristic that helps distinguish idiopathic PD from "Parkinson's Plus" and atypical Parkinson's syndromes-see below)
• persistent disabling symptoms (e.g. on troubling dyskinesias, or disabling "off" periods at least 3 hours/day) despite medication therapy. Patients will have been treated with variable doses of levodopa and dopamine agonists (at a minimum) and will have had an adequate trial of other adjunctive medications)
• stable on medical therapy for at least one month prior to study enrollment
• age >21
• available and willing to be followed-up according to study protocol

Exclusion Criteria:

• "Parkinson's plus" syndromes, secondary, or atypical Parkinson's syndromes (e.g. progressive supranuclear palsy, striato-nigral degeneration, multiple system atrophy, post-stroke, post-traumatic, or post-encephalitic Parkinson's. These patients have cardinal symptoms characteristic of PD but with additional symptoms indicating other organic brain dysfunction, such as gaze palsies, autonomic dysfunction, lack of response to L-dopa, these individuals tend not to improve with standard treatments for PD)
• previous Parkinson's Disease surgery
• medical contraindications to surgery or stimulation (e.g. uncontrolled hypertension, advanced coronary artery disease, other implanted stimulation or electronically-controlled devices including cardiac demand pacemaker, aneurysm clips, cochlear implants, or a spinal cord stimulator) (Note: for the subject who receives either a pacemaker and/or defibrillator after this study enrollment, he/she will be allowed to continue the study if the neurostimulator system can be adequately programmed to permit system compatibility)
• contraindication to magnetic resonance imaging (e.g. indwelling metal fragments or implants that might be affected by MRI)
• active alcohol or drug abuse
• score on Mini-Mental Status examination of 24 or lower, or other neuropsychological dysfunction 9e.g. dementia) that would contraindicate surgery
• intracranial abnormalities that would contraindicate surgery (e.g. stroke, tumor, vascular abnormality affecting the target area)
• pregnancy
• concurrent participation in another research protocol

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 22 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01076452
• Other Study ID Numbers: 468 Phase II; VA-NINDS-01 ( Other Identifier: NIH-NINDS )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: VA Office of Research and Development ( US Department of Veterans Affairs )
• Original Responsible Party: Follett, Kenneth - Study Chair, Department of Veterans Affairs
• Current Study Sponsor: US Department of Veterans Affairs
• Original Study Sponsor: Same as current

Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS)
• Medtronic

Investigators

• Study Chair: Kenneth Follett; VA Medical Center, Iowa City

• PRS Account: VA Office of Research and Development
• Verification Date: June 2014