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

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

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.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Device: Bilateral Deep Brain Stimulation

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
• Enrollment (Actual): 299
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90073
      • University of California at Los Angeles
    • San Francisco, California, United States, 94121
      • VA Medical Center, San Francisco
    • San Francisco, California, United States, 94121
      • University of California at San Francisco
    • West Los Angeles, California, United States, 90073
      • VA Greater Los Angeles Healthcare System, West LA
  • Iowa
    • Iowa City, Iowa, United States, 52246-2208
      • VA Medical Center, Iowa City
  • Oregon
    • Portland, Oregon, United States, 97201
      • VA Medical Center, Portland
    • Portland, Oregon, United States, 97207
      • Oregon Health Sciences University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Hospital
    • Philadelphia, Pennsylvania, United States, 19106
      • Philadelphia, OPC
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center (152)
  • Virginia
    • Richmond, Virginia, United States, 23249
      • Hunter Holmes McGuire VA Medical Center
    • Richmond, Virginia, United States, 23249
      • Medical College of Virginia
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System, Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: STN; Participants were randomized to receive deep brain stimulation on STN (Subthalamic Nucleus) target.	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.
Active Comparator: GPi; Participants were randomized to receive deep brain stimulation on GPi (Globus Pallidus) target.	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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change From Baseline in the UPDRS Scores Part I (Mentation) at 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.	Baseline and 24 months
The Change From Baseline in the UPDRS Scores Part II (Activity of Daily Living) at 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.	Baseline and 24 months
The Change From Baseline in the UPDRS Scores Part IV (Complication of Therapy) at 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.	Baseline and 24 months

Collaborators and Investigators

• Sponsor: US Department of Veterans Affairs
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Medtronic
• Investigators: Study Chair: Kenneth Follett, VA Medical Center, Iowa City

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2002
• Primary Completion (Actual): October 1, 2008
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: February 24, 2010
• First Submitted That Met QC Criteria: February 25, 2010
• First Posted (Estimate): February 26, 2010

Study Record Updates

• Last Update Posted (Estimate): July 14, 2014
• Last Update Submitted That Met QC Criteria: June 27, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Parkinson's Disease; dyskinesia; subthalamic nucleus; tremor; levo-dopa; globus pallidus
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: 468 Phase II; VA-NINDS-01 (Other Identifier: NIH-NINDS)