Parkinson's Disease
Conditions
Keywords
Early Stage Parkinson's Disease, Parkinson's Disease, Deep Brain Stimulation, PD, DBS
Brief summary
Bilateral subthalamic nucleus deep brain stimulation (B-STN DBS) is one of the most effective surgical treatments for PD patients suffering from levodopa-induced motor complications. The relatively low incidence of permanent adverse effects and the potential for neuroprotection and alteration of the natural course of PD suggest a highly favorable benefit-to-risk ratio of this procedure. Since neuroprotection is best applied early in the disease course when there are more surviving neurons, we believe that further investigation of this procedure is warranted. The proposed pilot study will provide the necessary data to substantiate the safety and tolerability of the procedure as well as provide data for the design of a full-scale, multicenter trial to investigate the hypothesis that B-STN DBS is a safe and effective treatment to slow the progression of PD.
Detailed description
This pilot trial is designed specifically to collect the preliminary safety and tolerability data necessary to conduct a future phase III clinical trial to investigate the hypothesis that deep brain stimulation of the subthalamic nucleus in subjects with early Parkinson's will slow the progression of the disease. The study design is a prospective, randomized, blinded, single-center trial comparing the safety and tolerability of B-STN DBS + Optimal Drug Therapy (ODT) vs. (ODT) alone (control, standard of care) in 30 subjects (15 per group) with early PD (Hoehn and Yahr stage II when off medication).
Interventions
DEVICEB-STN DBS
Deep brain stimulation (DBS) of both the right and left sub-thalamic nucleus (STN) is an FDA approved treatment for advanced PD. In mid- and advanced stage Parkinson's disease, using DBS in this area of the brain lessens symptoms and allows patients to take less drug to control the disease. Dosage and frequency are not applicable to the DBS. Once the DBS is placed, unless deemed necessary, it will not be removed.
DRUGOptimal drug therapy
The drugs used on this study are not investigational. They are drugs for Parkinson's disease that are standard of care. The drug form, dosage, frequency and duration will vary. Examples of drugs used include carbidopa/levodopa, pramipexole, ropinirole, and selegiline.
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have a clinical diagnosis of probable idiopathic PD. * Demonstrated response to dopaminergic therapy, defined as demonstrating at least 30% improvement in parkinsonian motor signs, based upon the UPDRS motor examination subscore, following the administration of their dopamine agonist (DA) drug(s) during the screening neurological examination. * Hoehn and Yahr (H&Y) stage II when OFF medication. * No contraindications to surgery. * Age between 50 and 75 years old. * Available for follow-up for four years. * Informed Consent: The subject understands the risks, benefits, and alternatives to the study procedures and participation in the study. * MRI within normal range for age. * Levodopa or dopamine agonist therapy for greater than six months but less than or equal to four years.
Exclusion criteria
* Evidence of an alternative diagnosis or secondary parkinsonism, as suggested by features unusual early in the clinical course: Prominent postural instability, freezing phenomena, or hallucinations unrelated to medications in the first 3 years after symptom onset; dementia preceding motor symptoms; supranuclear gaze palsy (other than restriction of upward gaze) or slowing of vertical saccades in the first year; severe, symptomatic dysautonomia unrelated to medications; documentation of a condition known to produce parkinsonism and plausibly connected to the subject's symptoms (such as suitably located focal brain lesions or neuroleptic use within the past 6 months) * Uncontrolled medical condition or clinically significant medical disease that would increase the risk of developing pre- or postoperative complications (e.g., significant cardiac or pulmonary disease, uncontrolled hypertension). * Evidence of dementia * Major psychiatric disorder * Previous brain operation or injury. * Active participation in another clinical trial for the treatment of PD. * Patients who have demand cardiac pacemakers or implantable cardioverter defibrillators (ICD's). * Patients who have medical conditions that require repeat MRI scans or diathermy treatments. * Evidence of existing dyskinesias or motor fluctuations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety: Time to Reach a 4 Point Increase (Worsening) in Unified Parkinson's Disease Rating Scale (UPDRS) Motor Score | baseline to 24 months | The primary hypothesis of this feasibility trial was focused on safety and tolerability and that the DBS+ODT group would not worsen more quickly than the ODT group. |
| Levodopa Equivalents, Change From Baseline | baseline to 24 months | 100 mg of levodopa with a dopa-decarboxylase inhibitor = 133 mg of controlled-release levodopa preparations = total levodopa dose + (total levodopa dose x 0.33) of levodopa with dopa-decarboxylase and entacapone = 1 mg of pergolide, pramipexole, or lisuride = 5 mg of ropinirole = 3.3 mg of rotigotine |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in UPDRS Part III, Motor Examination, Excluding Rigidity | baseline to 24 months | Score: 0-56 0 = full movement, 56 = most limited |
| Change in UPDRS Part I, Mentation Behavior and Mood | baseline to 24 months | Score: 0-16 0 =normal, 16 = most disability |
| Change in Total UPDRS | baseline to 24 months | The Total Unified Parkinson's Disease Rating Scale (UPDRS) is a composite scale, consisting of four sections that evaluate mood and behavior, activities of daily living, motor symptoms, and complications of medical therapy. Range is 0 to 16, with 16 being maximal disability |
| Change in UPDRS Part IV, Complications of Therapy | baseline to 24 months | Score: 0-23 0 =no complications, 23 = most complications |
| Change in UPDRS Part II, Activities of Daily Living | baseline to 24 months | Score: 0-52 0 =normal, 52 = most limited |
Participant flow
Pre-assignment details
7 participants excluded prior to treatment ( 1 withdrew consent and 6 failed screening)
Participants by arm
| Arm | Count |
|---|---|
| Optimal Drug Therapy (ODT) Patients receive optimal drug therapy as prescribed by their treating neurologist.
Optimal drug therapy: The drugs used on this study are not investigational. They are drugs for Parkinson's disease that are standard of care. The drug form, dosage, frequency and duration will vary. Examples of drugs used include carbidopa/levodopa, pramipexole, ropinirole, and selegiline. | 15 |
| Deep Brain Stimulation (DBS) Plus Optimal Drug Therapy (ODT) Subjects receive bilateral subthalamic nucleus (B-STN) DBS and continue to take optimal drug therapy as prescribed by their treating neurologist.
B-STN DBS: Deep brain stimulation (DBS) of both the right and left sub-thalamic nucleus (STN) is an FDA approved treatment for mid- and advanced PD. DBS is not approved for early stage PD. In mid- and advanced stage Parkinson's disease, using DBS in this area of the brain lessens symptoms and allows patients to take less drug to control the disease. Dosage and frequency are not applicable to the DBS. Once the DBS is placed, unless deemed necessary, it will not be removed.
Optimal drug therapy: The drugs used on this study are not investigational. They are drugs for Parkinson's disease that are standard of care. The drug form, dosage, frequency and duration will vary. Examples of drugs | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Optimal Drug Therapy (ODT) | Deep Brain Stimulation (DBS) Plus Optimal Drug Therapy (ODT) | Total |
|---|---|---|---|
| Age, Continuous | 60 years | 60 years | 60 years |
| Region of Enrollment United States | 15 participants | 15 participants | 30 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 13 Participants | 14 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 15 / 15 | 15 / 15 |
| serious Total, serious adverse events | 0 / 14 | 2 / 15 |
Outcome results
Primary
Levodopa Equivalents, Change From Baseline
100 mg of levodopa with a dopa-decarboxylase inhibitor = 133 mg of controlled-release levodopa preparations = total levodopa dose + (total levodopa dose x 0.33) of levodopa with dopa-decarboxylase and entacapone = 1 mg of pergolide, pramipexole, or lisuride = 5 mg of ropinirole = 3.3 mg of rotigotine
Time frame: baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Optimal Drug Therapy (ODT) | Levodopa Equivalents, Change From Baseline | 214.5 mg |
| Deep Brain Stimulation (DBS) Plus Optimal Drug Therapy (ODT) | Levodopa Equivalents, Change From Baseline | 97.7 mg |
Comparison: Study power was calculated based on the amount of PD medication consumed. We anticipated that the control group (ODT) would have a baseline value of 400 which would increase to 600, and that the treated group (DBS+ODT) would decrease from 400 to 300. A sample size of 12 patients per group (n=15, assuming 20% drop out) would have 80% power to detect a difference in means of 300 assuming that the common standard deviation is 250 using a two group t-test with a 0.05 two-sided significance level.p-value: 0.4t-test, 2 sided
Primary
Safety: Time to Reach a 4 Point Increase (Worsening) in Unified Parkinson's Disease Rating Scale (UPDRS) Motor Score
The primary hypothesis of this feasibility trial was focused on safety and tolerability and that the DBS+ODT group would not worsen more quickly than the ODT group.
Time frame: baseline to 24 months
Population: all 29 subjects that completed at least one follow up visit were included in the primary analysis following intent to treat principle
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Optimal Drug Therapy (ODT) | Safety: Time to Reach a 4 Point Increase (Worsening) in Unified Parkinson's Disease Rating Scale (UPDRS) Motor Score | 15 months |
| Deep Brain Stimulation (DBS) Plus Optimal Drug Therapy (ODT) | Safety: Time to Reach a 4 Point Increase (Worsening) in Unified Parkinson's Disease Rating Scale (UPDRS) Motor Score | 14.1 months |
p-value: 0.968Log Rank
Secondary
Change in Total UPDRS
The Total Unified Parkinson's Disease Rating Scale (UPDRS) is a composite scale, consisting of four sections that evaluate mood and behavior, activities of daily living, motor symptoms, and complications of medical therapy. Range is 0 to 16, with 16 being maximal disability
Time frame: baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Optimal Drug Therapy (ODT) | Change in Total UPDRS | 8.4 units on a scale |
| Deep Brain Stimulation (DBS) Plus Optimal Drug Therapy (ODT) | Change in Total UPDRS | 5.63 units on a scale |
Secondary
Change in UPDRS Part II, Activities of Daily Living
Score: 0-52 0 =normal, 52 = most limited
Time frame: baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Optimal Drug Therapy (ODT) | Change in UPDRS Part II, Activities of Daily Living | 2.3 units on a scale |
| Deep Brain Stimulation (DBS) Plus Optimal Drug Therapy (ODT) | Change in UPDRS Part II, Activities of Daily Living | 4.1 units on a scale |
Secondary
Change in UPDRS Part III, Motor Examination, Excluding Rigidity
Score: 0-56 0 = full movement, 56 = most limited
Time frame: baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Optimal Drug Therapy (ODT) | Change in UPDRS Part III, Motor Examination, Excluding Rigidity | 3.4 change in units on a scale |
| Deep Brain Stimulation (DBS) Plus Optimal Drug Therapy (ODT) | Change in UPDRS Part III, Motor Examination, Excluding Rigidity | 0.1 change in units on a scale |
Secondary
Change in UPDRS Part I, Mentation Behavior and Mood
Score: 0-16 0 =normal, 16 = most disability
Time frame: baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Optimal Drug Therapy (ODT) | Change in UPDRS Part I, Mentation Behavior and Mood | 1.1 units on a scale |
| Deep Brain Stimulation (DBS) Plus Optimal Drug Therapy (ODT) | Change in UPDRS Part I, Mentation Behavior and Mood | 1.2 units on a scale |
Secondary
Change in UPDRS Part IV, Complications of Therapy
Score: 0-23 0 =no complications, 23 = most complications
Time frame: baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Optimal Drug Therapy (ODT) | Change in UPDRS Part IV, Complications of Therapy | 1.9 units on a scale |
| Deep Brain Stimulation (DBS) Plus Optimal Drug Therapy (ODT) | Change in UPDRS Part IV, Complications of Therapy | 0.3 units on a scale |