This cohort study evaluates 5-year outcomes and safety of subthalamic nucleus deep brain stimulation for the treatment of Parkinson disease.
Key Points
Question
What are the long-term outcomes of subthalamic stimulation for the treatment of Parkinson disease (PD)?
Findings
In this open label phase of a randomized, sham-controlled, double-blinded trial, 137 patients with moderate to advanced PD receiving subthalamic stimulation observed significant improvements in motor function, suppression of dyskinesia, improvements in activities of daily living, and a reduction in anti-parkinsonian medications that were sustained over the 5-year follow-up period.
Meaning
These findings suggest that subthalamic deep brain stimulation (DBS) is an effective therapy for PD.
Abstract
Importance
The Implantable Neurostimulator for the Treatment of Parkinson’s Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD).
Objective
To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD.
Design, Setting, and Participants
This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson’s Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score.
Intervention
Bilateral STN-DBS for moderate to advanced PD.
Main Outcomes and Measures
Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs.
Results
A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P < .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P < .001). Activities of daily living without medication as measured by UPDRS-II improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P < .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P < .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P < .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P < .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P < .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study.
Conclusions and Relevance
Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.
Introduction
Deep brain stimulation (DBS) is widely recognized as a highly effective therapy for improving motor function and quality of life in patients with moderate to severe Parkinson disease (PD). INTREPID was designed as a multicenter, double-blind, randomized (3:1), sham-controlled study to provide class I evidence in support of subthalamic nucleus (STN)-DBS for the treatment of PD and to evaluate the outcomes and safety of a novel multiple independent constant current-controlled device designed to provide better control of current fields induced by stimulation. The 12-week results from the blinded phase of the study demonstrated improved on time, motor scale scores in the medication-off, stimulation-on state, quality of life, and treatment satisfaction.1
The study followed up randomized patients in a 5-year open-label phase to evaluate long-term safety and outcomes of the therapy. Here, we present the long-term results of this study.
Methods
Trial Design and Participants
This was a multicenter, parallel design, double-blind, randomized, sham-controlled study conducted at 23 sites across the US between May 2013 and December 2022. This study received approval from the US Food and Drug Administration and institutional review boards of each participating site. Participants provided written informed consent before enrollment. All data were collected by site personnel at the respective locations per study protocol (Supplement 1). Key inclusion criteria were being aged between 22 and 75 years, a diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, stable use of anti-parkinsonian medications for 28 days before consent, modified Hoehn and Yahr Scale score more than 2, Unified Parkinson’s Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and at least 33% improvement in UPDRS-III medication-on score. The trial was conducted in accordance with ISO 14155: Clinical Investigation of Medical Devices for Human Subjects—Good Clinical Practice; 21 CFR Part 812 and registered with ClinicalTrials.gov (NCT01839396).
Study Procedures and Follow-Up Assessments
A total of 313 participants provided informed consent, 210 underwent screening procedures and 193 were implanted with the Vercise DBS system (Boston Scientific). A detailed clinical protocol for the first phase of the trial was previously published1 describing eligibility criteria, screening, randomization, blinding, and evaluation of the primary end point.
Patients who met the previously stated criteria were randomized and blindly evaluated in the controlled phase of the study.1 Following the 12-week blinded period, 191 randomized participants transitioned into the open-label phase of the study, with the control group also receiving active stimulation (eFigure 1 in Supplement 2). During this phase, visits were scheduled at postrandomization week 20, 26, 48, 52 (±14 days), and 78 (±28 days) and at year 2, 3, 4, and 5 (±28 days).
Outcomes measured through 5 years postrandomization included UPDRS-I to IV (UPDRS-II and III were evaluated in both the medication-on and -off condition); change in anti-parkinsonian medication use (levodopa equivalent daily dose [LEDD])2; Clinical Dyskinesia Rating Scale (CDRS); Clinical Global Impression of Change (CGIC); Parkinson’s Disease Questionnaire-39 (PDQ-39); and the Treatment Satisfaction Questionnaire (eFigure 2 in Supplement 2). We also evaluated UPDRS-III subcategory motor signs, specifically rest tremor, postural tremor, rigidity, bradykinesia, and gait. Long-term follow-up end points with medication and stimulation status are described in Supplement 2. Safety parameters for long-term end points include rates of occurrence of adverse events (AEs) and serious adverse events (SAEs) through study completion.
Statistical Analysis
Descriptive statistics were used to summarize continuous variables, including the number of nonmissing observations, means, SDs, minimums, maximums, and 95% CIs. For categorical variables, frequencies and percentages were reported. Both primary and secondary outcomes were analyzed on an intention-to-treat basis, encompassing all randomly assigned patients. Patients with major predefined protocol deviations were excluded from the per-protocol analysis. The safety analysis included all enrolled patients.
For end points that address mean change from screening to 1 year, 2 years, 3 years, 4 years, and 5 years, a linear mixed model for repeated measures using an autoregressive covariance structure was used to compare assessments across time points adjusting for study site. The model contained fixed effects for visit and study site. The observed P value comparing screening vs 1 year and screening vs 5 years was reported for the following assessments: UPDRS (including part III motor subscores for tremor, bradykinesia, rigidity, and gait), PDQ-39, CDRS, and LEDD. Estimates and SEs of the mean (SEM) for each scheduled study visit were generated from the repeated measures model. We report the results with a box-and-whisker tail of 5% to 95%. All statistical analyses were completed using SAS version 9.4 (SAS Institute). For safety end points, all adverse events were coded using MedDRA, version 10.1 (ICH). A 2-sided P value less than .05 was considered statistically significant.
Results
A total of 193 participants were implanted with a DBS implantable pulse generator (IPG) with bilateral leads in the STN; 191 were randomized to receive either active therapeutic stimulation or subtherapeutic stimulation settings (control group) (eFigure 2 in Supplement 2). Of the 191 randomized participants, 137 (72%) completed the long-term follow-up per study schedule. Forty-five participants withdrew from the study, and most (29 participants) did so voluntarily. See eTable 1 in Supplement 2 for full listing of the reason for withdrawal.
There were 139 men (73.0%) and 52 women (27%) in the cohort (Table 1). Participants were diagnosed with bilateral idiopathic PD with a mean (SD) disease duration of 10.3 (3.8) years and a mean (SD) Hoehn and Yahr score of 2.8 (0.7). At screening, participants’ UPDRS-III scores in the medication-off condition had a mean (SEM) score of 42.8 (0.68), indicative of moderate PD. Compared with the medication-off condition, mean UPDRS-III scores in the medication-on condition improved by 57.5% (SEM, 0.58). As previously reported,1 INTREPID met its primary end point with a P < .001, showing a mean (SD) increase of 3.03 (4.52) hours in on time without troublesome dyskinesia from baseline to 3 months postrandomization between the active and control groups.
Table 1. Patient Demographics and Clinical Characteristics for Randomized Participants at Screening.
| Characteristic | Participants, No. (%) (N = 191) |
|---|---|
| Age at consent, mean (SD), y | 59.7 (7.9) |
| Age group | |
| <60 y | 84 (44) |
| 60-69 y | 88 (46) |
| ≥70 y | 19 (10) |
| Sex | |
| Female | 52 (27) |
| Male | 139 (73) |
| Parkinson disease–related symptoms | |
| Disease duration, mean (SD), y | 10.31 (3.8) |
| UPDRS-III medications-off, mean (SEM) | 42.8 (0.7) |
| UPDRS-III medications-on, mean (SEM) | 18.2 (0.6) |
| UPDRS-III percentage change from medications-off to screening medications-on, mean (SEM) | 57.5 (2.0) |
| Hoehn and Yahr stage (medications-on state), mean (SD) | 2.8 (0.7) |
| ≤2.0 | 49 (26) |
| 2.5 | 50 (26) |
| 3 | 63 (33) |
| 4 | 27 (14) |
| 5 | 2 (1) |
| Depression | |
| Minimal | 171 (90) |
| Mild | 19 (10) |
| Moderate | 1 (0.5) |
| Severe | 0 (0) |
| Levodopa equivalent daily dose, mean (SD), mg | 1455 (68) |
| PDQ-39 Summary Index, mean (SD) [No.] | 29 (13) [190] |
Abbreviations: PDQ-39, the Parkinson’s Disease Questionnaire; UPDRS-III, part 3 of the Unified Parkinson’s Disease Rating Scale.
Medication-Off, Stimulation-On Condition Postrandomization Follow-Up vs Medication-Off, Stimulation-Off Condition at Screening
In the 5-year follow-up, the mean UPDRS-III score showed an improvement of 51% (SEM, 0.779; P < .001) from screening to year 1 and a 36% (SEM, 1.050; P < .001) improvement relative to screening by year 5 (refer to Table 2 and Figure 1A for the year-by-year breakdown). Significant improvements were observed in the UPDRS-III subcategory motor scores for rest tremor, postural or action tremor, rigidity, bradykinesia, and gait under the medication-off, stimulation-on condition. Through 5 years, sustained improvements were observed for rest and postural or action tremor, and to a lesser extent for rigidity and bradykinesia (Figure 2; eTable 2 in Supplement 2). Mean rest and postural or action tremor scores revealed an 81% (SEM, 0.142; P < .001) and 67% (SEM, 0.09; P < .001) improvement from screening to year 1, respectively, and remained largely unchanged with a 76% (SEM, 0.187; P < .001) and 65% (SEM, 0.112; P < .001) improvement by year 5. Mean rigidity scores improved by 60% (SEM, 0.221; P < .001) in year 1 and by 47% (SEM, 0.339; P < .001) at year 5. Finally, mean bradykinesia scores showed a 42% (SEM, 0.066; P < .001) improvement in year 1, declining to 25% (SEM, 0.089; P < .001) improvement by year 5. Mean gait scores initially improved by 45% (SEM, 0.068; P < .001) at year 1 but declined to 11% improvement by year 5. Regarding activities of daily living (ADLs), the mean UPDRS-II score showed an improvement of 40% (SEM, 0.448; P < .001) from screening to year 1 and a 20% (SEM, 0.588; P < .001) improvement from screening to year 5 (Table 2; eFigure 3A in Supplement 2).
Table 2. Study End Points for Randomized Participants From Screening to 5 Years Postrandomization.
| Measure | Participants, mean (SD) [No.] | P value | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Screening stimulation off | Year 1a | Difference between screening and year 1 | Year 2a | Difference between screening and year 2 | Year 3a | Difference between screening and year 3 | Year 4a | Difference between screening and year 4 | Year 5a | Difference between screening and year 5 | Screening vs year 1 | Screening vs year 5 | |
| UPDRS-II scores medications-off | 20.64 (6.00) [191] | 12.35 (6.11) [185] | −8.37 (7.08) [185] | 13.77 (6.33) [176] | −6.97 (7.09) [176] | 14.81 (6.48) [165] | −6.21 (8.05) [165] | 15.80 (6.58) [140] | −5.30 (8.17) [140] | 16.41 (6.52) [122] | −4.65 (8.13) [122] | <.001 | <.001 |
| UPDRS-III scores medications-off | 42.81 (9.38) [191] | 21.05 (10.58) [185] | −21.81 (12.51) [185] | 21.86 (11.34) [177] | −20.93 (13.29) [177] | 22.43 (11.58) [166] | −20.61 (14.09) [166] | 25.28 (11.51) [140] | −17.16 (13.83) [140] | 27.63 (11.61) [122] | −15.02 (12.90) [122] | <.001 | <.001 |
| UPDRS-I scores medications-on | 2.08 (1.64) [190] | 2.15 (1.92) [184] | 0.07 (2.09) [183] | 2.50 (1.99) [177] | 0.41 (2.07) [176] | 2.89 (2.18) [165] | 0.87 (2.41) [164] | 3.14 (2.06) [142] | 1.00 (2.34) [142] | 3.47 (2.26) [124] | 1.44 (2.50) [124] | .63 | <.001 |
| UPDRS-II scores medications-on | 8.85 (5.28) [191] | 8.86 (5.77) [177] | −0.03 (6.19) [177] | 10.22 (6.48) [169] | 1.53 (6.90) [169] | 11.96 (6.56) [155] | 3.26 (7.30) [155] | 12.92 (6.36) [134] | 4.46 (6.56) [134] | 15.01 (6.27) [114] | 6.23 (6.32) [114] | .97 | <.001 |
| UPDRS-III scores medications-on | 18.21 (7.99) [191] | 15.01 (9.10) [175] | −3.17 (10.18) [175] | 15.81 (10.04) [167] | −2.54 (10.94) [167] | 16.91 (10.18) [153] | −1.52 (11.40) [153] | 17.73 (10.31) [135] | −0.34 (11.10) [135] | 20.37 (10.56) [114] | 1.53 (11.08) [114] | <.001 | .01 |
| UPDRS-IV scores medications-on | 8.78 (3.00) [191] | 3.86 (2.65) [184] | −4.95 (3.48) [184] | 3.85 (3.00) [178] | −4.90 (3.82) [178] | 4.09 (2.67) [164] | −4.71 (3.66) [164] | 4.33 (2.70) [142] | −4.44 (3.64) [142] | 4.68 (3.02) [123] | −3.96 (3.64) [123] | <.001 | <.001 |
| CDRS hyperkinesias medications-on | 4.00 (5.07) [191] | 0.99 (2.06) [184] | −3.05 (4.96) [184] | 1.10 (2.39) [179] | −2.92 (5.35) [179] | 1.36 (2.88) [166] | −2.57 (5.40) [166] | 1.19 (2.52) [142] | −2.44 (4.96) [142] | 1.20 (2.06) [124] | −2.94 (5.61) [124] | <.001 | <.001 |
| CDRS dystonias medications-on | 0.98 (2.12) [188] | 0.46 (1.26) [183] | −0.53 (2.15) [180] | 0.61 (1.62) [179] | −0.35 (2.31) [176] | 0.69 (1.60) [166] | −0.15 (2.00) [163] | 0.82 (1.85) [142] | −0.11 (2.61) [140] | 1.07 (2.23) [124] | 0.14 (2.82) [121] | <.001 | .54 |
| Anti-parkinsonian medications (LEDD, mg) | 1455 (934.4) [191] | 1052 (754.8) [182] | −428 (972.7) [182] | 1068 (836.3) [170] | −395 (911.6) [170] | 1079 (863.8) [158] | −407 (952.9) [158] | 1147 (850.7) [138] | −348 (959.2) [138] | 1043 (705.9) [121] | −407 (910.2) [121] | <.001 | <.001 |
| PDQ-39 summary index | 28.74 (12.99) [190] | 19.56 (12.28) [185] | −9.15 (14.58) [184] | 22.22 (13.05) [180] | −6.46 (15.39) [179] | 23.02 (14.06) [165] | −5.66 (15.42) [164] | 25.42 (13.37) [142] | −3.27 (15.43) [141] | 27.29 (14.32) [126] | −1.86 (16.02) [126] | <.001 | .18 |
| Schwab and England | 83.44 (9.47) [189] | 85.52 (10.77) [183] | 1.99 (13.48) [181] | 83.31 (12.20) [178] | −0.23 (14.77) [176] | 81.94 (14.31) [165] | −2.09 (16.79) [163] | 79.30 (16.01) [142] | −4.44 (17.69) [142] | 78.32 (16.79) [125] | −5.65 (17.73) [124] | NA | NA |
| EQ-5D-5L index value | 0.75 (0.14) [189] | 0.78 (0.11) [185] | 0.02 (0.14) [183] | 0.76 (0.13) [179] | 0.00 (0.17) [177] | 0.75 (0.13) [165] | 0.00 (0.17) [163] | 0.74 (0.14) [141] | −0.02 (0.17) [140] | 0.72 (0.15) [124] | −0.03 (0.21) [124] | NA | NA |
| EQ-5D-5L visual analog score | 70.88 (16.76) [189] | 0.78 (0.11) [185] | 76.36 (15.88) [185] | 73.85 (15.69) [179] | 2.64 (20.34) [177] | 72.44 (16.52) [165] | 1.75 (22.30) [163] | 73.64 (13.83) [142] | 2.71 (21.09) [140] | 71.53 (16.76) [125] | 1.86 (22.48) [124] | NA | NA |
| Clinical global impression of changeb | NA | 91.3% (168/184) | NA | 87.2% (156/179) | NA | 86.1% (143/166) | NA | 88.0% (125/142) | NA | 80.2% (101/126) | NA | NA | NA |
| Clinical global impression of change c | NA | 95.1% (174/183) | NA | 94.9% (167/176) | NA | 93.9% (154/164) | NA | 92.1% (129/140) | NA | 88.1% (111/126) | NA | NA | NA |
| Clinical global impression of change d | NA | 84.3% (86/102) | NA | 84.1% (74/88) | NA | 78.8% (52/66) | NA | 79.6% (39/49) | NA | 80.9% (38/47) | NA | NA | NA |
| Treatment satisfaction | NA | 6.63 (1.80) [185] | NA | 6.64 (1.64) [180] | NA | 6.87 (1.47) [164] | NA | 6.92 (1.26) [142] | NA | 6.94 (1.44) [126] | NA | NA | NA |
| SF-36 PCS | 38.55 (7.55) [190] | 42.84 (8.86) [184] | 4.24 (9.09) [183] | 41.11 (9.08) [180] | 2.57 (9.00) [179] | 40.61 (8.72) [166] | 1.79 (9.21) [165] | 40.47 (8.99) [142] | 1.09 (9.74) [141] | 38.57 (9.50) [125] | −0.20 (10.56) [125] | NA | NA |
| SF-36 MCS | 50.57 (7.91) [190] | 52.20 (8.48) [184] | 1.61 (9.45) [183] | 50.84 (8.77) [180] | 0.02 (9.99) [179] | 51.08 (9.37) [166] | 0.34 (10.42) [165] | 50.81 (9.08) [142] | 0.53 (10.22) [141] | 51.54 (8.98) [125] | 1.07 (9.67) [125] | NA | NA |
Abbreviations: CDRS, Clinician-Dependent Rating Scale; EQ-5D-5L, EuroQol 5-Dimension 5-Level; LEDD, levodopa equivalent daily dose; NA, not applicable; PDQ-39, Parkinson’s Disease Questionnaire; SF-36 MCS, Short Form 36 Health Survey Mental Component; SF-36 PCS, Short Form 36 Health Survey Physical Component; UPDRS I-IV, Unified Parkinson’s Disease Rating Scale Parts I-IV.
Postrandomization.
Number of patients with improvement as assessed by participant.
Number of patients with improvement as assessed by physician.
Number of patients with improvement as assessed by caregiver.
Figure 1. Outcomes at Screening up to 5 Years Postrandomization for Unified Parkinson’s Disease Rating Scale (UPDRS-III) Motor Scores, Parkinsonian-Medicine Usage, Patient Satisfaction With Treatment, and Quality Of Life.
A, UPDRS-III motor scores: the y-axis indicates mean UPDRS-III scores in the stimulation-on and medications-off condition. Box and whiskers indicate 5% to 95% tails, and diamond indicates mean). From screening, a significant improvement in motor outcomes is reported 1 year after deep brain stimulation (DBS) and sustained out to 5 years. B, levodopa equivalent daily dose (LEDD) in mg: the y-axis indicates mean LEDD from screening through the 5-year follow-up at each screening and yearly visit. Box and whiskers indicate 5% to 95% tails, and diamond indicates mean. From screening, there is a statistically significant reduction in medication 1 year after DBS implant sustained out to 5 years. C, Treatment Satisfaction Questionnaire: participants rated their satisfaction and if they would recommend the treatment to a friend with Parkinson disease. The y-axis shows the percentage of participants expressing satisfaction or dissatisfaction with DBS treatment, with different degrees of satisfaction or dissatisfaction indicated by shades of blue (satisfied) or orange (dissatisfied). On average, 94% of participants were satisfied while 6% of participants were dissatisfied across the 5-year follow-up. Error bars represent SE of the mean. D, Quality of life (Parkinson's Disease Questionnaire-39 [PDQ-39] index score): the PDQ-39 index score is derived from 39 items grouped into the 8 domains shown. Each item is scored on a 5-point Likert scale, with scores ranging from 0 (no problems at all) to 100 (maximum level of problems). The index score is the mean of the 8 individual scale scores. Improvement in this score returned to screening values by year 5 (5% improvement; P = .18). The most pronounced sustained improvements at year 5 are seen in the domains of bodily discomfort, activities of daily living, and stigma.
aP < .001 for screening vs year 1 and screening vs year 5.
Figure 2. Evaluation of Unified Parkinson’s Disease Rating Scale (UPDRS-III) Motor Symptom Subcategories at Screening and Year 1 and Year 5 Postrandomization.
Screening in medication-off condition only but year 1 and year 5 are medication-off, stimulation-on condition. The y-axis indicates mean score from screening through year 1 and year 5 postrandomization. Box and whiskers indicate 5% to 95% tails, diamond indicates mean.
aP < .001.
Medication-On, Stimulation-On Condition Postrandomization Follow-Up vs Medication-On, Stimulation-Off Condition at Screening
In the medication-on stimulation-on condition, the mean UPDRS-III score showed an improvement of 18% (SEM, 0.688; P < .001) from screening to year 1 and a worsening of 12% (SEM, 1.0; P = .01) from screening to year 5 (Table 2). However, significant improvements were observed in the UPDRS-III subcategory motor scores for rest tremor, postural or action tremor, and rigidity under the medication-on and stimulation-on condition (eTable 2 in Supplement 2). Mean rest and postural or action tremor scores showed an improvement of 67% (SEM, 2.91; P < .001) and 47% (SEM, 11.29; P < .001) from screening to year 1, respectively, and remained largely unchanged with an improvement of 65% (SEM, 3.69; P < .001) and 41% (SEM, 15.16; P < .001) from screening to year 5, respectively. Mean rigidity score showed an improvement of 46% (SEM, 8.16; P < .001) from screening to year 1 and 22% (SEM, 8.69; P < .001) by year 5. Bradykinesia and gait scores showed no improvements in the medication-on stimulation-on condition compared with screening. The mean UPDRS-IV score in the medication-on stimulation-on condition, which measures treatment-related motor complications, showed an improvement of 56% (SEM, 5.06; P < .001) from screening to year 1, which was maintained at 47% improvement (SEM, 5.82; P < .001) at year 5 (Table 2).
CDRS hyperkinesia scores improved 75% (SEM, 0.15; P < .001) from screening to year 1 and maintained a 70% improvement (SEM, 0.19; P < .001) from screening to year 5. Mean LEDD scores showed a 28% (SEM, 55.95; P < .001) decrease from screening to year 1 that was maintained with a 28% (SEM, 64.17; P < .001) decrease from screening to year 5 (Table 2, Figure 1B).
Neither UPDRS-I nor II scores showed any improvement in the medication-on, stimulation-on condition. For UPDRS-I, mean scores worsened by 3% and 67% (SEM, 0.203; P < .001) from screening to year 1 and year 5, respectively. Similarly, mean UPDRS-II scores showed virtually no change from screening to year 1 but worsened by 70% (SEM, 0.587; P < .001) at year 5 (Table 2; eFigure 3B in Supplement 2).
Quality of Life, Patient Satisfaction, and Impression of Change Measurements
Regarding quality of life, sustained improvements were observed at year 1 within some of the PDQ-39 domains (eTable 3 in Supplement 2; Figure 1D) including stigma at 55% (SEM, 1.18; P < .001), bodily discomfort at 36% (SEM, 1.43; P < .001), and ADLs at 46% (SEM, 1.27; P < .001). At year 5, stigma remained improved at 43% (SEM, 1.72; P < .001), bodily discomfort was moderately improved at 19% (SEM, 1.93; P < .001), and there was a 20% improvement for ADLs (SEM, 1.86; P < .001). Although unchanged in year 1, the domain of communication worsened over time.
PDQ-39 Summary Index showed a 32% improvement in the quality of life for patients at year 1 (Table 2) (SEM, 0.903; P < .001). There was a gradual decline in quality of life over the subsequent years returning to screening (5% improvement at year 5).
Patient satisfaction was assessed using a structured questionnaire over the 5-year period. Most patients experienced high levels of satisfaction with treatment, with 94% expressing satisfaction and 6% expressing dissatisfaction across the 5 years (Table 2, Figure 1C). This trend remained consistent throughout the 5-year period.
The CGIC scale was used to assess changes in a patient’s condition over time as perceived by the participant, physician, and caregiver. The scores indicated that all 3 groups perceived an improvement in the patients’ conditions over the 5-year period (Table 2; eFigure 4 in Supplement 2). The mean percentage of participants who perceived an improvement was 87% (SEM, 1.8), and it was 93% (SEM, 1.3) for physicians and 82% (SEM, 2.1) for caregivers. Throughout the 5-year period, all groups consistently maintained a perception of patient improvement ranging from 80% to 88% (eFigure 4 in Supplement 2). For other quality of life assessments, see Table 2.
Safety
The primary safety end point of INTREPID, which included the rates of occurrence of prespecified adverse device effects at year 1 postrandomization and surgical complications in the 196 patients implanted with the DBS system, was reported previously.1 A total of 1136 AEs were reported in 182 participants. Of these, 945 were nonserious, occurring in 173 participants, with the majority being unrelated to the study device or implant procedure. The most common nonserious AEs, with 10 or more instances each, included dyskinesia (34 participants), implant site edema (18 participants), falls (13 participants), balance disorder (14 participants), and tremor (10 participants) (eTable 4 in Supplement 2).
There were 191 SAEs reported in 98 participants with 66 related to the study. These included events related to hardware (22 participants), stimulation (2 participants), and procedure (eTable 5 in Supplement 2). The most frequently reported SAE related to the device or procedure was infection, occurring in 9 participants, 8 of which required surgery to resolve. One suicide attempt was attributed to the implant procedure and stimulation. There were 2 instances of cerebral hemorrhage associated with neurological sequalae and 4 instances of seizure.
To date, 10 deaths have been reported that can be attributed to PD (4 participants), cardiac events (2 participants), physical trauma injury (1 participant), hypoxia (1 participant), failure to thrive (1 participant), and cerebral hemorrhage (1 participant). None of the reported deaths were study-related.
Discussion
The INTREPID study demonstrated the use of a multiple independent current control DBS IPG system that resulted in improvements in motor function, suppression of dyskinesia, improvements in ADLs, and a reduction in anti-parkinsonian medications that were sustained over the 5-year follow-up period. These findings support the long-term outcomes of STN-DBS to improve motor function, reduce motor fluctuations, lower anti-parkinsonian medication use, and treat dyskinesia in PD patients.
The patient population in this study is comparable with those in previous controlled trials for STN-DBS regarding age and disease duration.2,3,4 Recent trials reported mean ages of 60 to 63 years and disease durations of 12 to 13 years, while INTREPID reported 90% of patients under the age of 69 and a mean disease duration of 10 years at time of screening.
UPDRS-III in the medication-off, stimulation-on condition was included among the powered secondary end points, as these are the standard metrics used in the literature and defined by Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease (CAPSIT-PD) standards.5 STN-DBS for PD studies from the early 2000s have reported UPDRS-III score improvements over screening levels in the medications-off condition of 49% after 5 years,6 28% to 66% at end points of at least 6 months,7 and by 52% over an unspecified period.8 Subsequent large, multicenter randomized clinical trials have provided additional evidence of effectiveness, reporting UPDRS-III score improvements in the medications-off condition by 25% to 58% over periods of 6 to 24 months.2,3,4,9,10,11,12
This study shows comparable motor benefits with a mean 51% improvement in UPDRS-III motor scores in the medication-off, stimulation-on condition after 1 year, sustained with a 36% improvement out to 5 years. In a de novo PD cohort, Holden et al13 reported UPDRS-III scores increased in a linear fashion over 5 years (2.4-point increase year-over-year). In INTREPID, we observed a similar trend in UPDRS-III in the medication-off, stimulation-on condition over the 5 years (approximately 1.6-point increase year-over-year), while maintaining a significant and sustained improvement compared with screening.
Analysis of UDPRS-III subcategories showed sustained improvement in tremor, rigidity, and bradykinesia; to a lesser degree, gait scores in the medication-off, stimulation-on condition; and tremor and rigidity under the medication-on stimulation-on condition. While tremor, rigidity, and dyskinesia remained well controlled, bradykinesia, gait, and other aspects of motor performance such as postural instability gradually worsened. This is not surprising as PD is a progressive neurodegenerative disorder and motor performance deteriorates with disease progression. INTREPID is notable for being one of the largest studies examining the outcomes of STN-DBS on long-term clinical outcomes in a diverse cohort reflecting various clinical practices and management approaches. The results of this study align with prior studies that used smaller cohorts, all showing sustained improvement in motor function when comparing the medication-off, stimulation-on condition with screening in the medication-off state. In the only blinded prospective cohort study, Castrioto et al14 assessed 18 patients with advanced PD who underwent bilateral STN-DBS. Patients were videotaped at baseline, 1, 5, and 10 years postsurgery, with motor evaluations conducted by an independent rater blinded to both stimulation and medication conditions. At 10 years, in the medication-off condition, STN-DBS improved the UPDRS-III score by 25.3%, with rest and postural tremor subscores improving by 85% and 87.5%, respectively, and bradykinesia subscores by 23.1% compared with the stimulation-off condition. Other long-term nonblinded studies of STN DBS for PD have reported improvement in UPDRS III scores in the stimulation-on medication-off state of 54% to 55% at 5 years,15,16,17 39% at 8 years,17 and 38.5% at 11 years.18
Although UPDRS II scores in the medication-off, stimulation-on condition remained improved over the 5-year period, similar to UPDRS III scores, they gradually worsened over time. While the improvement decreased over 5 years, as reflected in the progressive worsening of ADL II scores in the medication-on stimulation-on state, this observation is consistent with disease progression and worsening of medication unresponsive symptoms such as speech, gait, balance, and swallowing. This observation was also reflected in the quality-of-life assessment (PDQ-39 SI), where we observed initial improvement that gradually worsened to a 5% improvement at year 5.
The high level of patient satisfaction in this cohort was reflected in the CGIC scores, where patients, physicians, and caregivers perceived significant and sustained improvements over 5 years. A consistent trend of improvement or stability can be observed across all 3 evaluators, suggesting a positive response to treatment. Discrepancies between the different evaluators’ scores, however, highlight the importance of considering multiple perspectives in clinical evaluations.
While INTREPID was not designed to evaluate the potential benefit of DBS earlier in the course of the disease, 52% of the patients in INTREPID reported a baseline Hoehn and Yahr score of 2.5 or less, while most previous studies only included patients with scores above 3.0. Since INTREPID, other studies, notably the Controlled Trial with Deep Brain Stimulation in Patients with Early Parkinson's Disease (EARLYSTIM) trial,11 have shown that DBS at earlier stages of PD yields significant clinical advantages, thereby broadening the range of eligibility for patients receiving this treatment. Current trials are now exploring the application of DBS in patients who are fairly well managed with medication and do not experience motor fluctuations.19 As DBS procedures continue to advance in safety and consistency of benefit, it is likely more patients will consider DBS earlier in the course of their disease.
Limitations
This study had several limitations. The lack of a control group during the open-label phase limits the ability to attribute long-term outcomes solely to DBS, as other factors, such as changes in medication, disease progression, or environmental factors beyond study control (eg, COVID-19) could also influence results. We did not do diary studies beyond year 1, so changes in good on time (ie, on time without troublesome dyskinesia) were not assessed long-term. Additionally, since the inception and completion of INTREPID, advances to DBS technology such as directional DBS leads and newer IPGs have been developed that may aid us in addressing the observed loss of efficacy or diminished quality of life that occurred over time in INTREPID. Furthermore, new tools are available to aid in implantation and programming of DBS systems, such as patient-specific image-guided programming20,21 and use of neurophysiological biomarkers,22,23 which have been gaining traction in recent years and are starting to provide better symptom management in PD patients. Lastly, identification of the optimal location for DBS leads in the target structure, a better understanding of DBS mechanisms and the role of fiber pathway activation models in targeting and programming of DBS devices will all likely play a more critical role in advancing these procedures in the future.
Conclusion
Collectively, our results illustrate that while the degree of improvement in UPDRS-III scores may diminish over time (probably due to disease regression), STN-DBS continues to provide significant long-term motor benefits for PD patients. This therapy not only enhances quality of life in the short term but also maintains its efficacy in managing motor symptoms and reduces the need for anti-parkinsonian medication and dyskinesia while improving ADLs over many years.
Trial Protocol
eAppendix. Endpoints for Long-Term Follow Up
eFigure 1. Participant Disposition
eFigure 2. INTREPID Study Design Schematic
eFigure 3. Longitudinal Assessment of Activities of Daily Living (UPDRS II), Over 5 Years
eFigure 4. Longitudinal Assessment of Clinical Global Impression of Change Scores by Participant, Physician, and Caregiver, Over Five Years
eTable 1. Reasons for Withdrawal of ParticipantAfter Randomization
eTable 2. Mean Change in UPDRS III Subcategory Questions From Screening to 1, 2, 3, 4, and 5 Years Postrandomization
eTable 3. Mean Change in PDQ-39 Domains From Screening to 1, 2, 3, 4, and 5 Years Postrandomization
eTable 4. Nonserious Adverse Events (>10) in all Implanted Participants (N=196) During the Entire 5-Year Follow-Up Study
eTable 5. Serious Adverse Events Related to DBS Hardware, Stimulation, or Procedure for all Implanted Participants (N=196) During the 5 Year Follow-Up Period
Nonauthor Collaborators
Data Sharing Statement
References
- 1.Vitek JL, Jain R, Chen L, et al. Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson’s disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study. Lancet Neurol. 2020;19(6):491-501. doi: 10.1016/S1474-4422(20)30108-3 [DOI] [PubMed] [Google Scholar]
- 2.Weaver FM, Follett K, Stern M, et al. ; CSP 468 Study Group . Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009;301(1):63-73. doi: 10.1001/jama.2008.929 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Deuschl G, Schade-Brittinger C, Krack P, et al. ; German Parkinson Study Group, Neurostimulation Section . A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2006;355(9):896-908. doi: 10.1056/NEJMoa060281 [DOI] [PubMed] [Google Scholar]
- 4.Okun MS, Gallo BV, Mandybur G, et al. ; SJM DBS Study Group . Subthalamic deep brain stimulation with a constant-current device in Parkinson’s disease: an open-label randomised controlled trial. Lancet Neurol. 2012;11(2):140-149. doi: 10.1016/S1474-4422(11)70308-8 [DOI] [PubMed] [Google Scholar]
- 5.Defer GL, Widner H, Marié RM, Rémy P, Levivier M. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord. 1999;14(4):572-584. doi: 10.1002/1531-8257(199907)14:4<572::AID-MDS1005>3.0.CO;2-C [DOI] [PubMed] [Google Scholar]
- 6.Hamani C, Richter E, Schwalb JM, Lozano AM. Bilateral subthalamic nucleus stimulation for Parkinson’s disease: a systematic review of the clinical literature. Neurosurgery. 2005;56(6):1313-1321. doi: 10.1227/01.NEU.0000159714.28232.C4 [DOI] [PubMed] [Google Scholar]
- 7.Pahwa R, Factor SA, Lyons KE, et al. ; Quality Standards Subcommittee of the American Academy of Neurology . Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):983-995. doi: 10.1212/01.wnl.0000215250.82576.87 [DOI] [PubMed] [Google Scholar]
- 8.Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord. 2006;21(S14)(suppl 14):S290-S304. doi: 10.1002/mds.20962 [DOI] [PubMed] [Google Scholar]
- 9.Follett KA, Weaver FM, Stern M, et al. ; CSP 468 Study Group . Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2010;362(22):2077-2091. doi: 10.1056/NEJMoa0907083 [DOI] [PubMed] [Google Scholar]
- 10.Odekerken VJ, van Laar T, Staal MJ, et al. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson’s disease (NSTAPS study): a randomised controlled trial. Lancet Neurol. 2013;12(1):37-44. doi: 10.1016/S1474-4422(12)70264-8 [DOI] [PubMed] [Google Scholar]
- 11.Schuepbach WMM, Rau J, Knudsen K, et al. ; EARLYSTIM Study Group . Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med. 2013;368(7):610-622. doi: 10.1056/NEJMoa1205158 [DOI] [PubMed] [Google Scholar]
- 12.Williams A, Gill S, Varma T, et al. ; PD SURG Collaborative Group . Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol. 2010;9(6):581-591. doi: 10.1016/S1474-4422(10)70093-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Holden SK, Finseth T, Sillau SH, Berman BD. Progression of MDS-UPDRS scores over five years in de novo Parkinson disease from the Parkinson’s progression markers initiative cohort. Mov Disord Clin Pract. 2018;5(1):47-53. doi: 10.1002/mdc3.12553 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Castrioto A, Lozano AM, Poon YY, Lang AE, Fallis M, Moro E. Ten-year outcome of subthalamic stimulation in Parkinson disease: a blinded evaluation. Arch Neurol. 2011;68(12):1550-1556. doi: 10.1001/archneurol.2011.182 [DOI] [PubMed] [Google Scholar]
- 15.Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 2003;349(20):1925-1934. doi: 10.1056/NEJMoa035275 [DOI] [PubMed] [Google Scholar]
- 16.Gervais-Bernard H, Xie-Brustolin J, Mertens P, et al. Bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease: five year follow-up. J Neurol. 2009;256(2):225-233. doi: 10.1007/s00415-009-0076-2 [DOI] [PubMed] [Google Scholar]
- 17.Fasano A, Romito LM, Daniele A, et al. Motor and cognitive outcome in patients with Parkinson’s disease 8 years after subthalamic implants. Brain. 2010;133(9):2664-2676. doi: 10.1093/brain/awq221 [DOI] [PubMed] [Google Scholar]
- 18.Rizzone MG, Fasano A, Daniele A, et al. Long-term outcome of subthalamic nucleus DBS in Parkinson’s disease: from the advanced phase towards the late stage of the disease? Parkinsonism Relat Disord. 2014;20(4):376-381. doi: 10.1016/j.parkreldis.2014.01.012 [DOI] [PubMed] [Google Scholar]
- 19.Hacker ML, Tonascia J, Turchan M, et al. Deep brain stimulation may reduce the relative risk of clinically important worsening in early stage Parkinson’s disease. Parkinsonism Relat Disord. 2015;21(10):1177-1183. doi: 10.1016/j.parkreldis.2015.08.008 [DOI] [PubMed] [Google Scholar]
- 20.Lange F, Steigerwald F, Malzacher T, et al. Reduced programming time and strong symptom control even in chronic course through imaging-based DBS programming. Front Neurol. 2021;12:785529. doi: 10.3389/fneur.2021.785529 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Torres V, Del Giudice K, Roldán P, et al. Image-guided programming deep brain stimulation improves clinical outcomes in patients with Parkinson’s disease. NPJ Parkinsons Dis. 2024;10(1):29. doi: 10.1038/s41531-024-00639-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Quinn EJ, Blumenfeld Z, Velisar A, et al. Beta oscillations in freely moving Parkinson’s subjects are attenuated during deep brain stimulation. Mov Disord. 2015;30(13):1750-1758. doi: 10.1002/mds.26376 [DOI] [PubMed] [Google Scholar]
- 23.Oehrn CR, Cernera S, Hammer LH, et al. Chronic adaptive deep brain stimulation versus conventional stimulation in Parkinson’s disease: a blinded randomized feasibility trial. Nat Med. 2024;30(11):3345-3356. doi: 10.1038/s41591-024-03196-z [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eAppendix. Endpoints for Long-Term Follow Up
eFigure 1. Participant Disposition
eFigure 2. INTREPID Study Design Schematic
eFigure 3. Longitudinal Assessment of Activities of Daily Living (UPDRS II), Over 5 Years
eFigure 4. Longitudinal Assessment of Clinical Global Impression of Change Scores by Participant, Physician, and Caregiver, Over Five Years
eTable 1. Reasons for Withdrawal of ParticipantAfter Randomization
eTable 2. Mean Change in UPDRS III Subcategory Questions From Screening to 1, 2, 3, 4, and 5 Years Postrandomization
eTable 3. Mean Change in PDQ-39 Domains From Screening to 1, 2, 3, 4, and 5 Years Postrandomization
eTable 4. Nonserious Adverse Events (>10) in all Implanted Participants (N=196) During the Entire 5-Year Follow-Up Study
eTable 5. Serious Adverse Events Related to DBS Hardware, Stimulation, or Procedure for all Implanted Participants (N=196) During the 5 Year Follow-Up Period
Nonauthor Collaborators
Data Sharing Statement
