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Deep brain stimulation may reduce the relative risk of clinically important worsening in early stage Parkinson's disease
Parkinsonism and Related Disorders 21 (2015) 1177e1183
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Deep brain stimulation may reduce the relative risk of clinically important worsening in early stage Parkinson's disease Mallory L. Hacker a, *, James Tonascia b, Maxim Turchan a, Amanda Currie a, Lauren Heusinkveld a, Peter E. Konrad c, Thomas L. Davis a, Joseph S. Neimat c, Fenna T. Phibbs a, Peter Hedera a, Lily Wang d, Yaping Shi d, David M. Shade b, Alice L. Sternberg b, Lea T. Drye b, David Charles a a
Department of Neurology, Vanderbilt University, 1611 21st Ave S., A-0118 Medical Center North, Nashville, TN, 37232-2551, United States Department of Epidemiology, Johns Hopkins University, 615 N Wolfe St., Baltimore, MD, 21205, United States c Department of Neurosurgery, Vanderbilt University, 4340 Village at Vanderbilt, Nashville, TN, 37232-8618, United States d Department of Biostatistics, Vanderbilt University, 2525 West End Avenue, Suite 11000, Nashville, TN, 37212, United States b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 May 2015 Received in revised form 9 July 2015 Accepted 9 August 2015
Background: The Vanderbilt pilot trial of deep brain stimulation (DBS) in early Parkinson's disease (PD) enrolled patients on medications six months to four years without motor fluctuations or dyskinesias. We conducted a patient-centered analysis based on clinically important worsening of motor symptoms and complications of medical therapy for all subjects and a subset of subjects with a more focused medication duration. Continuous outcomes were also analyzed for this focused cohort. Methods: A post hoc analysis was conducted on all subjects from the pilot and a subset of subjects taking PD medications 1e4 years at enrollment. Clinically important worsening is defined as both a 3 point increase in UPDRS Part III and a 1 point increase in Part IV. Results: DBS plus optimal drug therapy (DBS þ ODT) subjects experienced a 50e80% reduction in the relative risk of worsening after two years. The DBS þ ODT group was improved compared to optimal drug therapy (ODT) at each time point on Total UPDRS and Part III (p ¼ 0.04, p ¼ 0.02, respectively, at 24 months). Total UPDRS, Part IV, and PDQ-39 scores significantly worsened in the ODT group after two years (p < 0.003), with no significant change in the DBS þ ODT group. Conclusions: DBS þ ODT in early PD may reduce the risk of clinically important worsening. These findings further confirm the need to determine if DBS þ ODT is superior to medical therapy for managing symptoms, reducing the complications of medications, and improving quality of life. The FDA has approved the conduct of a large-scale, pivotal clinical trial of DBS in early stage PD. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Deep brain stimulation Subthalamic nucleus
1. Introduction After completing a prospective, single-blind pilot trial of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in very early stage Parkinson's disease (PD) [1], Vanderbilt University received FDA approval to conduct a prospective, double-blind, placebo-controlled, pivotal, multicenter, phase III, clinical trial evaluating safety and efficacy of DBS early PD. Experience and data from the pilot study were used to inform the design and endpoints of the pivotal trial. Pre-submission meetings with staff at both the
* Corresponding author. E-mail address: [email protected] (M.L. Hacker). http://dx.doi.org/10.1016/j.parkreldis.2015.08.008 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
NIH and the FDA resulted in recommendations to refocus the pivotal trial with a primary endpoint that would be clinically meaningful to patients considering early DBS therapy. We therefore established a patient-centered composite outcome evaluating two important features of early PD: motor symptoms and complications of medical therapy. Minimum clinically important differences for the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor examination) and Part IV (complications of medical therapy) are 2.3e2.7 and 0.7, respectively [2,3]. These reported differences on components of this validated PD measure [4,5] were used to inform the decision to establish a per-patient change over two years that would be clinically meaningful. An individual subject's clinically important worsening is defined as both a 3 point increase in
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UPDRS Part III ON and a 1 point increase on Part IV. Here, we report analysis of the DBS in early PD pilot using this composite outcome to evaluate the risk of clinically important worsening on measures meaningful to both patients and physicians weighing early DBS implantation. Additionally, results of the primary analysis of the DBS in early PD pilot showed that scores on Part IV diverge between the groups at 24 months, with the DBS plus optimal drug therapy (DBS þ ODT) group relatively unchanged from baseline (þ0.30) while the optimal drug therapy (ODT) control group worsened by two-fold (þ1.9 points) [1]. Complications of medical therapy become increasingly disabling as PD progresses [6], and stabilization of Part IV scores after two years of stimulation in early PD suggests this outcome may be an appropriate endpoint for a pivotal trial. During the design of the phase III clinical trial, members of a CTSAsupported studio raised concerns that enrolling subjects on medication for less than one year may include early PD subjects who would complete the two-year study period before ever being at risk for developing dyskinesias or other motor complications. Similar concerns were expressed by Ahlskog and colleagues [7], who comment that including patients “prior to when motor complications would be expected” would “underestimate frequencies” of motor fluctuations and dyskinesias. A future efficacy trial evaluating Part IV that includes PD patients on medication less than one year could be negatively impacted by a floor effect of this assessment of the complications of medical therapy. Members of the studio suggested that enrolling subjects on medication 1e4 years would better focus the study population on the currently available clinical measures and also have the added benefit of potentially decreasing the likelihood of enrolling participants who would later prove to not have idiopathic PD. We therefore conducted a post hoc analysis of the pilot study of DBS in early stage PD to evaluate outcomes in a more focused study population to provide the data needed to select appropriate endpoints and power the future pivotal, phase III safety and efficacy clinical trial. 2. Methods A prospective, single-blind, randomized, parallel-group, placebo-controlled pilot trial of DBS in early PD (NCT#00282152) that was approved by the FDA (IDE#G050016) and the Vanderbilt University IRB (IRB#040797) completed in 2012 [1]. The pilot study enrolled idiopathic PD patients, age 50e75, Hoehn & Yahr Stage II OFF medication, taking PD medications for 6 months to 4 years at enrollment, without any history of dyskinesias or other motor fluctuations. Here, we conducted a patient-centered outcomes analysis for all subjects with baseline and 24 month UPDRS Part III and IV scores (n ¼ 28) and also for the recommended focused cohort of subjects with medication duration of 1e4 years at enrollment (n ¼ 20). Continuous outcomes were also analyzed for subjects in this focused cohort and compared to published outcomes for the DBS in early PD pilot trial [1]. Pilot study randomization occurred independent of PD medication duration, and therefore, the randomization of subjects in the subset analysis is not compromised by the use of a more focused medication duration. 2.1. Design Detailed descriptions of the study design, enrollment experience, baseline characteristics, and surgical methods for the DBS in early PD pilot trial are published elsewhere [8e12]. Briefly, the pilot trial enrolled early stage idiopathic PD patients, age 50e75, without dyskinesias or other motor fluctuations who provided written informed consent. Subjects who passed screening were admitted
into the Clinical Research Center (CRC) for an eight-day evaluation. On day one in the ON therapy state, a series of PD measures were collected including the Total UPDRS (with Part III videotaped). Subjects' PD medication regimens were also recorded and converted to levodopa equivalents [13], and a battery of neuropsychological tests (including the Parkinson's disease questionnaire39 (PDQ-39) quality of life assessment) was administered. After a seven-day washout (day 8), a subset of measures from day one were collected again in the OFF therapy state (including videotaped Part III). Subjects were then randomized to receive either DBS þ ODT or ODT. Participants randomized to receive DBS þ ODT underwent bilateral STN DBS surgery [9,12]. All subjects returned to the CRC for the same week-long therapy washout every six months during the two-year study period, and the neuropsychological battery was administered annually. 2.2. Statistical analysis Relative risk reductions (DBS þ ODT vs ODT) in the rates of clinically important composite worsening of both PD motor symptoms and complications of medical therapy are expressed as RRR ¼ 100 (1rDBSþODT/rODT), where rDBSþODT and rODT are the rates of composite PD worsening in the DBS þ ODT and ODT groups, respectively. Values of RRR between 0 and 100% favor the DBS group. The RRRs, 95% confidence limits, and P-values were calculated using Stata 13 Software for comparison of incidence rates (IR command) in 2 2 tables using ManteleHaenzel methods. Continuous outcomes were summarized using mean and standard deviation at baseline, 6 month, 12 month, 18 month and 24 month for DBS þ ODT and ODT groups. The changes for the two groups as well as the group difference in changes between each time point from baseline were estimated using mixed effects models that included group effect, time effect (as a factor) and group by time interaction while accounting for the correlations within subject. Parameter estimate, 95% confidence interval and p value were provided. All analyses were implemented using R 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). A significance level of 0.05 was used for statistical inference. 3. Results We conducted a patient-centered outcomes analysis on all subjects from the pilot study and also on the focused cohort on medication 1e4 years at enrollment (Table 1). When data from all subjects in the pilot trial were evaluated, 54% of the ODT group and only 27% of the DBS þ ODT group experienced clinically important worsening after two years. This difference translates to a 50% relative risk reduction for the DBS þ ODT group compared to the ODT group (P ¼ 0.25). Furthermore, when this method was applied to the focused cohort of subjects in the DBS in early PD pilot trial on medication 1e4 years at enrollment, there was an 80% reduction in the risk of clinically important worsening experienced by the DBS þ ODT group compared to the ODT group (P ¼ 0.07). We also analyzed continuous outcomes for the DBS þ ODT and ODT groups in a more focused cohort of subjects from the pilot trial, with a medication duration of 1e4 years. There were no significant differences between the groups at baseline (Table S1), and baseline characteristics for subjects included in this analysis were similar to those from the primary analysis [1]. Outcomes for each group at baseline and 24 months are listed in Table 2. Total UPDRS scores from baseline to 24 months for the ODT group significantly worsened (þ9.68 points; p < 0.003; Table S2), while the DBS þ ODT group scores were unchanged (0.2 points). Change from baseline scores for Total UPDRS was better for the DBS group at every time point (Fig. 1A; p < 0.05 at 24 months).
M.L. Hacker et al. / Parkinsonism and Related Disorders 21 (2015) 1177e1183
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Table 1 Relative risk reduction (RRRs) for clinically important worsening in both the motor symptoms and the complications of medical therapy for PD. PD medication duration at enrollment 6 monthse4 years (n ¼ 28a)
Treatment assignment
(1) Clinically worse motor symptoms: 3 increase in UPDRS Part III on
(2) Clinically worse complications of medical therapy: 1 increase in UPDRS Part IV
(3) Composite worsening of PD: both (1) and (2)
ODT (n ¼ 13a) DBS þ ODT (n ¼ 15)
54% 47%
85% 47%
54% 27%
Relative risk reductions in composite clinical worsening (DBS þ ODT vs ODT)
50% 95% CI 0.19e1.32 P ¼ 0.25 1e4 years (n ¼ 20) ODT (n ¼ 11) DBS þ ODT (n ¼ 9)
55% 33%
82% 44%
55% 11% 80% 95% CI 0.03e1.40 P ¼ 0.07
a
Baseline UPDRS Part III On score missing for 1 ODT subject who was excluded from this analysis.
DBS þ ODT group Part III ON scores were improved from baseline at each time point, and after two years of treatment, these motor scores were 3.8 points better in the DBS þ ODT group and 4.1 points worse in the ODT group (Fig. 1B). Part III ON change from baseline scores favored the DBS þ ODT group at each six month evaluation (p < 0.03 at 6, 12, and 24 months). The ODT group scores on Part IV increased by 1.8 at 24 months (p < 0.003; Table S2), with minimal change (þ0.3) in the DBS þ ODT group after two years (Fig. 1C; p > 0.05). Scores on the patient-reported PDQ-39 quality of life assessment significantly declined in the ODT group after 24 months (þ11.5 points; p < 0.001; Table S2), and a between-group comparison revealed that the ODT group worsened by an average of 6.1 points more than the DBS þ ODT group at 24 months (Fig. 1D). Additionally, the DBS þ ODT group was significantly better than the ODT group on change scores at 24 months on the PDQ-39 dimensions of emotional well-being and stigma (p < 0.05). Fig. 2 illustrates the between-group differences in mean change scores at 24 months on the Total UPDRS, PDQ-39 Summary Index, and their respective subscores for subjects on medication 6 months to 4 years [1] and the subset on medication 1e4 years (Table 2). As reported in the primary analysis of all subjects in the DBS in early PD pilot study [1], Total UPDRS, UPDRS Part III ON and OFF, UPDRS Part II OFF, and UPDRS Part IV scores for the DBS þ ODT group were better than the ODT group after two years (orange line, Fig. 2A). These between-group differences are more pronounced when the study population is focused to subjects on PD medications 1e4 years (blue line, Fig. 2A). Similarly, trends observed in analysis of dimensions of the PDQ-39 quality of life assessment are amplified when the inclusion criteria are focused to subjects on medications 1e4 years (Fig. 2B). Furthermore, four out of five PDQ-39 subscores that are highly influenced by motor aspects of PD (activities of daily living, emotional wellbeing, stigma, and bodily discomfort [14]) are each more than 8 points better in the DBS þ ODT group after two years in the present analysis.
4. Discussion Our analysis of a patient-centered outcome evaluating motor features combined with complications of medical therapy suggests that early stage PD subjects treated with medications alone are 2e5 times more likely to experience clinically important worsening than subjects treated with DBS þ ODT (Table 1). Focusing the
inclusion criteria on early PD subjects with a medication duration of 1e4 years revealed a particularly striking 80% reduction in the relative risk of symptom worsening for the DBS þ ODT group. DBS therapy is well-known to improve motor symptoms and reduce the complications of medical therapy in advanced stage PD, and these benefits of DBS þ ODT over ODT were also seen in mid-stage PD [15]. The reduction in the relative risk of clinically important worsening on motor symptoms and complications of medical therapy observed in analysis of the pilot trial of DBS in early PD is consistent with the well-documented superiority of DBS þ ODT over ODT in PD stages that have been tested thus far. Additionally, comparing continuous outcomes from the pilot trial for all subjects and the subset on medication 1e4 years demonstrates that focusing the study population accentuates trends previously observed [1]. This comparison suggests that including PD patients on medication less than one year may have muted between-group differences (Fig. 2). These results suggest that focusing the study population in early stage PD moved scores into meaningful ranges for the wellestablished and validated outcome measures currently used to evaluate PD. Taken together, these analyses support future utilization of this inclusion criterion with this patient-centered composite outcome in trials of DBS in early PD.
4.1. DBS þ ODT is superior to standard medical therapy for the treatment of motor symptoms in early PD Two independent outcomes from this analysis suggest DBS þ ODT is superior to standard care for treating motor symptoms in early PD. First, the changes from baseline in the UPDRS Part III ON scores are better in the DBS þ ODT group than ODT at each time point, with two year change scores improving 15% in the DBS þ ODT group and worsening 19% in the ODT group (Fig. 1B). This assessment, which evaluates the cardinal motor features of PD, was scored by an independent, blinded neurologist in the pilot trial [1] (Fig. 1B). Second, the patient-reported PDQ-39 assessment also favors DBS þ ODT over ODT (Table 2), particularly on dimensions that are highly influenced by motor aspects of PD: activities of daily living, emotional well-being, stigma, and bodily discomfort [14] (Fig. 2B). The superior efficacy of DBS plus medication when compared to ODT for the treatment of motor features of advanced stage PD is well established [16e18]. Criticisms of the ethics of evaluating DBS in early PD frequently center on the assertion that
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Table 2 Baseline and 24 months outcomes. Outcome
DBS þ ODT (n ¼ 9) Baseline
a b c d e f g h i
24 month
Mean difference (95% CI)
Mean difference (95% CI)
Mean difference (95% CI)
P Value
2.18 (0.25) 2.14 (0.23)
0.36 (0.15e0.58) 0.14 (0.02e0.25)
0.14 (0.46e0.19) 0.08 (0.09e0.25)
0.41 0.35
2.22 (6.36e1.92) 2.22 (6.19e1.75)
90 (5.92) 89.09 (5.84)
85.45 (9.61) 85.5 (6.85)
4.55 (8.29e0.80) 3.18 (6.88e0.51)
2.32 (7.9e3.26) 0.96 (6.39e4.47)
0.41 0.73
1.11 (0.08e2.14)
1.77 (1.21)
3.27 (1.9)
1.5 (0.57e2.43)
8.45 (4.93) 10.09 (4.11)
10.73 (6.39) 14.91 (5.2)
2.27 (0.11e4.66) 4.82 (2.14e7.5)
21.09 30.91 2.45 33.77
25.18 41 4.27 43.45
2.17 (0.25) 2.11 (0.22)
0.5 (0.26e0.74) 0.06 (0.07e0.18)
92.78 (4.41) 88.89 (3.33)
90.56 (7.26) 86.67 (7.5)
1.22 (1.3)
2.33 (2.0)
8.89 (4.81) 10.56 (4.48)
11.06 (6.32) 13 (5.96)
26 30.75 1.78 37.89
22.22 39.67 2.11 37.72
(11.65) (11.31) (1.27) (17.4)
24 month
1.82 (0.4) 2 (0.0)
1.67 (0.5) 2.06 (0.17)
(12.22) (10.21) (1.64) (16.39)
Baseline
MIDa
ODT minus DBS þ ODT
2.17 (0.47e4.81) 2.44 (0.52e5.41) 3.78 9.3 0.33 0.17
(8.73e1.17) (4.28e14.32) (0.93e1.6) (6.97e6.63)
(9.89) (8.32) (1.86) (14.14)
(9.63) (9.14) (2.00) (16.49)
4.09 10.09 1.82 9.68
(0.39e8.57) (5.72e14.46) (0.67e2.97) (3.53e15.83)
0.39 (1e1.78)
0.58
0.11 (3.45e3.66) 2.37 (1.63e6.37)
0.95 0.25
2e3c 2e3c
7.87 0.79 1.48 9.85
0.02 0.82 0.09 0.04
2.5e, 5g, 6.2h 2.5e, 5g, 6.2h 0.7f 8d,g
(1.19e14.54) (5.86e7.45) (0.23e3.19) (0.68e19.02)
5.93 (17.8) 17.25 (31.53)
3.26 (8.62) 10.06 (15.67)
2.68 (14.66e9.3) 0.05 (15.02e15.12)
0.0 (0.0) 13.63 (16.12)
4.12 (11.67) 7.14 (14.15)
4.12 (7.15e15.4) 4.25 (18.4e9.89)
64.56 (13.61) 54.44 (14.93)
72 (17.21) 54.33 (25.78)
7.44 (0.58e14.31) 0.11 (8.1e7.93)
67.91 (16) 57.36 (10.33)
69.64 (18.29) 55.82 (21.3)
1.73 (4.48e7.94) 1.55 (8.82e5.72)
5.72 (14.97e3.54) 1.43 (12.27e9.4)
0.23 0.80
65 (11.08) 59.33 (10.11)
68.44 (13.44) 55.89 (10.42)
3.44 (2.48e9.37) 3.44 (9.74e2.85)
63.09 (12.14) 55.36 (12.65)
65.73 (17.38) 55.73 (19.81)
2.64 (2.72e7.99) 0.36 (5.33e6.05)
0.81 (8.79e7.18) 3.81 (4.68e12.29)
0.84 0.38
18.78 (3.27) 21 (4.87) 475.67 (323.09)
18.33 (3.77) 23.12 (5.19) 620.44 (327.25)
19.55 (3.86) 21.09 (3.99) 479.27 (242.72)
18.27 (3.66) 21 (5.66) 596.09 (283.08)
1.27 (3.69e1.15) 0.18 (4.33e3.98) 116.82 (46.63e280.27)
11.94 14.82 11.11 7.64 7.41 11.11 11.11 16.67 11.47
(15.09) (15.61) (8.33) (13.18) (16.37) (7.51) (9.32) (13.82) (7.76)
23.33 19.44 10.64 8.33 6.48 22.22 22.21 21.3 16.83
(25.53) (20.94) (7.83) (8.84) (10.02) (18.78) (18.16) (15.09) (11.37)
MID ¼ Minimally Important Difference. Excludes rigidity. UPDRS Total reported as the sum of UPDRS Parts I, II, III, and IV. UPDRS Total reported as the sum of UPDRS Parts I, II, and III. Ref. [2]. Ref. [3]. Ref. [20]. Ref. [21]. Ref. [25].
0.44 (3.12e2.23) 2.84 (1.79e7.47) 144.78 (35.92e325.48)
11.39 4.63 0.47 0.69 0.92 11.11 11.1 4.63 5.36
(0.04e22.74) (7.73e16.98) (8.6e7.67) (7.91e9.3) (8.48e6.63) (0.18e22.04) (0.3e21.9) (6.99e16.25) (0.49e11.2)
11.82 17.04 14.01 14.77 3.79 20.45 9.85 22.73 14.31
(15.81) (17.33) (13.34) (20.01) (5.73) (13.72) (6.26) (15.41) (9.5)
22.27 30.68 26.89 28.41 8.33 27.27 27.27 35.6 25.82
(25.6) (29.24) (23.23) (27.58) (12.91) (17.06) (22.7) (21.44) (18.55)
10.45 13.63 12.88 13.64 4.55 6.82 17.43 12.87 11.51
(0.19e20.72) (2.46e24.81) (5.52e20.24) (5.86e21.42) (2.29e11.38) (3.07e16.71) (7.66e27.19) (2.36e23.39) (6.22e16.8)
6.8 (9.65e23.25) 4.3 (24.97e16.37)
0.83 (4.43e2.78) 3.02 (9.24e3.2) 27.96 (271.61e215.69)
0.93 9.01 13.35 12.94 5.47 4.29 6.32 8.24 6.15
(16.24e14.37) (7.66e25.67) (2.38e24.31) (1.34e24.54) (4.72e15.66) (19.04e10.45) (8.24e20.88) (7.42e23.91) (1.73e14.04)
0.42 0.68
0.65 0.34 0.82
0.91 0.29 0.02 0.03 0.29 0.57 0.40 0.30 0.13
3.2i 4.4i 4.2i 5.6i 11.4i 1.8i 4.2i 2.1i 1.6i
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Hoehn & Yahr ON OFF Schwab & England ON OFF UPDRS I II “ON” medication “OFF” medication IIIb ON OFF IV Totalc ON/OFF Diaries ON with dyskinesias OFF Finger taps Dominant hand ON OFF Non-dominant nand ON OFF Stand-walk-sit (s) ON OFF Levodopa equivalents (mg) Quality of life PDQ-39 Mobility Activities of daily living Emotion well being Stigma Social support Cognition Communication Bodily discomfort Single index
ODT (n ¼ 11)
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Fig. 1. Change from baseline scores on Total UPDRS, UPDRS Part III ON, UPDRS Part IV, and PDQ-39 Summary Index. Mean change (D) from baseline scores (SEM) on key PD measures over the two year pilot study period: (A) Total UPDRS, (B) UPDRS Part III ON (motor examination; excluded rigidity), (C) UPDRS Part IV (complications of medical therapy), (D) PDQ-39 (quality of life). z within-group comparison p < 0.03, * between-group comparison p < 0.04 (Table S2).
Fig. 2. Trends observed in analysis of all subjects from the DBS in early PD pilot study are amplified by focusing the inclusion criteria. Spider diagrams show change from baseline to 24 month scores (ODT minus DBS þ ODT) on (A) the UPDRS and (B) the PDQ-39 and their respective subscores from analysis of all subjects in the pilot study (orange lines; [1]) and the present analysis (blue lines; Table 1). The DBS þ ODT group scores are better than ODT for domains with positive values (gray), and the ODT are better than DBS þ ODT for domains with negative values (red). Green PDQ-39 subscores are highly influenced by motor aspects of PD [14].
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early stage PD symptoms are adequately managed by medical therapy and that the potential for DBS-mediated improvements is outweighed by the risks associated with surgery. The combination of blinded clinician-rated and patient-reported outcome measures demonstrating DBS þ ODT is superior to ODT offers strong evidence that there is considerable room for improvement in treatment options for early stage PD. 4.2. Limitations Although data from the pilot study of DBS in early stage PD were prospectively collected [1], this analysis is limited by its use of post hoc comparisons. Another limitation of this dataset is its small sample size. However, this sample size reduction did not increase the variability of the data (Table 2) compared to the primary analysis [1], which suggests this analysis was conducted on a more homogenous sample of early stage PD subjects. Although the assessments used in the pilot study are well established, validated outcome measures for Parkinson's disease, potential floor effects may restrict their utility in very early stage PD. Additionally, the pilot trial was open-label for all measures except for a single-blind assessment of UPDRS Part III, and outcomes reported may have been influenced by knowledge of treatment assignment through placebo or lessebo effects [19]. The pivotal trial design approved by the FDA addresses this concern by making the best attempt at conducting double-blind study. STN-DBS therapy for advanced PD significantly improves motor symptoms and quality of life while reducing medication requirements [16e18]. Analysis of all subjects from the DBS in early PD pilot trial showed less medication utilization in the DBS þ ODT group compared to ODT [1]. However, this reduced medication requirement with DBS þ ODT versus ODT was not observed in the analysis of the focused cohort (Table 2). The small sample size of the focused analysis may have precluded detection of the expected medication reduction (n ¼ 20). The role STN-DBS plays on reducing the medication burden of early stage PD will be evaluated in the large-scale, phase III, pivotal trial. 4.3. Meaningful differences on PD outcome measures This analysis offers preliminary data to inform the design of a large, multicenter study evaluating safety and efficacy of DBS þ ODT in early stage PD. By focusing the study population on subjects with medication duration of 1e4 years, this analysis shows that clinically meaningful differences on established PD outcome measures could be achieved in early stage PD. The improvement of DBS þ ODT over ODT on the change in UPDRS motor score (Part III) in this analysis was statistically significant at 6, 12, and 24 months (p < 0.02; Table S2). The between-group difference in the change scores on this blinded, clinician-rated measure was 7.9 points, which well exceeds minimal clinically important changes reported for UPDRS Part III [2,20,21] (Table 2). The ODT group experienced a significant worsening of UPDRS Part IV (complications of medical therapy) after 24 months (p < 0.003), with a minimal change in the DBS þ ODT group after two years (p ¼ 0.63). This between-group difference for the change from baseline to 24 months of 1.5 is twice the reported minimal important change for Part IV (Table 2) [3]. Although some PD medications, such as amantadine [22,23] or memantine [24], are suggested to diminish motor fluctuations, these medications were not used to treat a sufficient number of subjects over the two year-study period to impact the results (one ODT subject was treated with amantadine). Although the PDQ-39 quality of life summary index scores increased for both groups after two years, the ODT group experienced significant worsening from baseline to 24 months (Fig. 1D;
p < 0.001) with minimal change in the DBS þ ODT group from months 12e24. A minimal important difference for the PDQ-39 summary index is reported to be 1.6 [25], and the between-group difference on the 24 month change scores was better in the DBS þ ODT group by more than three times this reported minimal difference. Subanalysis of PDQ-39 reveals that the difference in the summary index scores is largely driven by the domains of activities of daily living, emotional well-being, stigma, and bodily discomfort/ pain (Fig. 2; Table 2). Between-group differences on each of these dimensions favored the DBS þ ODT group by more than 8 points and exceeded minimal important differences from two-to four-fold (Table 2) [25]. Of note, between-group cognition scores on the PDQ-39 favored ODT over DBS þ ODT by a minimal important difference (Table 2) [25]. Neuropsychological and cognitive decline is an established consequence of PD [26], and concerns exist related to DBS in limited domains [27,28]. A detailed neuropsychological analysis of the DBS in early PD cohort is reported elsewhere [29]. Recent evidence suggests that the surgical procedure, not active stimulation, may be responsible for a limited cognitive decline if present [30]. The double-blind design of the pivotal trial approved by the FDA will allow for a direct comparison of the effect of surgery versus STN stimulation to further enlighten the source of the cognitive impairment in PD patients treated with DBS þ ODT. These results suggest that DBS in early PD reduces the relative risk of clinically important worsening and is superior to medication alone for treating motor symptoms, reducing the complications of medical therapy, and providing better quality of life. Additional study is need to confirm these findings, and the FDA has approved this focused inclusion criteria and patient-centered outcome in a prospective, pivotal, phase III, multicenter, double-blind, placebocontrolled clinical trial designed to definitively discern whether DBS is superior to medication alone in early PD. Acknowledgments We thank our study coordinator, Odessa Lankford, for her dedication and commitment to the trial. Research reported in this publication was supported by Medtronic, Inc., by Vanderbilt CTSA grant UL1TR000445 from the National Center for Advancing Translational Sciences (NCATS), by NCATS/NIH award UL1TR000011, by NIH R01 EB006136, by private donations and by The Michael J. Fox Foundation for Parkinson's Research. Medtronic representatives did not take part in data collection, management, analysis, or interpretation of the data or in preparation, review, or approval of the manuscript. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2015.08.008. References [1] D. Charles, P.E. Konrad, J.S. Neimat, A.L. Molinari, M.G. Tramontana, S.G. Finder, C.E. Gill, M.J. Bliton, C. Kao, F.T. Phibbs, Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease, Parkinsonism Relat. Disord. 20 (2014) 731e737. [2] L.M. Shulman, A.L. Gruber-Baldini, K.E. Anderson, P.S. Fishman, S.G. Reich, W.J. Weiner, The clinically important difference on the Unified Parkinson's Disease Rating Scale, Arch. Neurol. 67 (2010) 64e70. [3] H. Honig, A. Antonini, P. Martinez-Martin, I. Forgacs, G.C. Faye, T. Fox, K. Fox, F. Mancini, M. Canesi, P. Odin, Intrajejunal levodopa infusion in Parkinson's disease: a pilot multicenter study of effects on nonmotor symptoms and quality of life, Mov. Disord. 24 (2009) 1468e1474. [4] P. Martinez-Martin, A. Gil-Nagel, L.M. Gracia, J.B. Gomez, J. Martinez-Sarries, F. Bermejo, Unified Parkinson's Disease Rating Scale characteristics and structure. The cooperative multicentric group, Mov. Disord. 9 (1994) 76e83.
M.L. Hacker et al. / Parkinsonism and Related Disorders 21 (2015) 1177e1183 [5] A. Siderowf, M. McDermott, K. Kieburtz, K. Blindauer, S. Plumb, I. Shoulson, Test-retest reliability of the Unified Parkinson's Disease Rating Scale in patients with early Parkinson's disease: results from a multicenter clinical trial, Mov. Disord. 17 (2002) 758e763. [6] J.A. Obeso, M.C. Rodriguez-Oroz, P. Chana, G. Lera, M. Rodriguez, C.W. Olanow, The evolution and origin of motor complications in Parkinson's disease, Neurology 55 (2000) S13eS20 discussion S21eS13. [7] J.E. Ahlskog, M.D. Muenter, Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature, Mov. Disord. 16 (2001) 448e458. [8] P. Charles, R. Dolhun, C. Gill, T. Davis, M. Bliton, M. Tramontana, R. Salomon, L. Wang, P. Hedera, F. Phibbs, Deep brain stimulation in early Parkinson's disease: enrollment experience from a pilot trial, Parkinsonism Relat. Disord. 18 (2012) 268e273. [9] E. Kahn, P.-F. D'Haese, B. Dawant, L. Allen, C. Kao, P.D. Charles, P. Konrad, Deep brain stimulation in early stage Parkinson's disease: operative experience from a prospective randomised clinical trial, J. Neurol. Neurosurg. Psychiatry 83 (2012) 164e170. [10] M.S. Remple, C.H. Bradenham, C.C. Kao, P.D. Charles, J.S. Neimat, P.E. Konrad, Subthalamic nucleus neuronal firing rate increases with Parkinson's disease progression, Mov. Disord. 26 (2011) 1657e1662. [11] D. Charles, C. Tolleson, T.L. Davis, C.E. Gill, A.L. Molinari, M.J. Bliton, M.G. Tramontana, R.M. Salomon, C. Kao, L. Wang, Pilot study assessing the feasibility of applying bilateral subthalamic nucleus deep brain stimulation in very early stage Parkinson's disease: study design and rationale, J. Parkinsons Dis. 2 (2012) 215e223. [12] C.R. Camalier, P.E. Konrad, C.E. Gill, C. Kao, M.R. Remple, H.M. Nasr, T.L. Davis, P. Hedera, F.T. Phibbs, A.L. Molinari, J.S. Neimat, D. Charles, Methods for surgical targeting of the STN in early-stage Parkinson's disease, Front. Neurol. 5 (2014) 25. [13] C.L. Tomlinson, R. Stowe, S. Patel, C. Rick, R. Gray, C.E. Clarke, Systematic review of levodopa dose equivalency reporting in Parkinson's disease, Mov. Disord. 25 (2010) 2649e2653. [14] G. Deuschl, Y. Agid, Subthalamic neurostimulation for Parkinson's disease with early fluctuations: balancing the risks and benefits, Lancet Neurol. 12 (2013) 1025e1034. [15] W. Schuepbach, J. Rau, K. Knudsen, J. Volkmann, P. Krack, L. Timmermann, €lbig, H. Hesekamp, S. Navarro, N. Meier, Neurostimulation for Parkinson's T. Ha disease with early motor complications, New Engl. J. Med. 368 (2013) 610e622. [16] G. Deuschl, C. Schade-Brittinger, P. Krack, J. Volkmann, H. Schafer, K. Botzel, C. Daniels, A. Deutschlander, U. Dillmann, W. Eisner, D. Gruber, W. Hamel, J. Herzog, R. Hilker, S. Klebe, M. Kloss, J. Koy, M. Krause, A. Kupsch, D. Lorenz, S. Lorenzl, H.M. Mehdorn, J.R. Moringlane, W. Oertel, M.O. Pinsker, H. Reichmann, A. Reuss, G.H. Schneider, A. Schnitzler, U. Steude, V. Sturm, L. Timmermann, V. Tronnier, T. Trottenberg, L. Wojtecki, E. Wolf, W. Poewe, J. Voges, NS German Parkinson study group, a randomized trial of deep-brain stimulation for Parkinson's disease, N. Engl. J. Med. 355 (2006) 896e908. [17] F.M. Weaver, K. Follett, M. Stern, K. Hur, C. Harris, W.J. Marks, J. Rothlind, O. Sagher, D. Reda, C.S. Moy, Bilateral deep brain stimulation vs best medical
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Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Deep brain stimulation may reduce the relative risk of clinically important worsening in early stage Parkinson's disease Mallory L. Hacker a, *, James Tonascia b, Maxim Turchan a, Amanda Currie a, Lauren Heusinkveld a, Peter E. Konrad c, Thomas L. Davis a, Joseph S. Neimat c, Fenna T. Phibbs a, Peter Hedera a, Lily Wang d, Yaping Shi d, David M. Shade b, Alice L. Sternberg b, Lea T. Drye b, David Charles a a
Department of Neurology, Vanderbilt University, 1611 21st Ave S., A-0118 Medical Center North, Nashville, TN, 37232-2551, United States Department of Epidemiology, Johns Hopkins University, 615 N Wolfe St., Baltimore, MD, 21205, United States c Department of Neurosurgery, Vanderbilt University, 4340 Village at Vanderbilt, Nashville, TN, 37232-8618, United States d Department of Biostatistics, Vanderbilt University, 2525 West End Avenue, Suite 11000, Nashville, TN, 37212, United States b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 May 2015 Received in revised form 9 July 2015 Accepted 9 August 2015
Background: The Vanderbilt pilot trial of deep brain stimulation (DBS) in early Parkinson's disease (PD) enrolled patients on medications six months to four years without motor fluctuations or dyskinesias. We conducted a patient-centered analysis based on clinically important worsening of motor symptoms and complications of medical therapy for all subjects and a subset of subjects with a more focused medication duration. Continuous outcomes were also analyzed for this focused cohort. Methods: A post hoc analysis was conducted on all subjects from the pilot and a subset of subjects taking PD medications 1e4 years at enrollment. Clinically important worsening is defined as both a 3 point increase in UPDRS Part III and a 1 point increase in Part IV. Results: DBS plus optimal drug therapy (DBS þ ODT) subjects experienced a 50e80% reduction in the relative risk of worsening after two years. The DBS þ ODT group was improved compared to optimal drug therapy (ODT) at each time point on Total UPDRS and Part III (p ¼ 0.04, p ¼ 0.02, respectively, at 24 months). Total UPDRS, Part IV, and PDQ-39 scores significantly worsened in the ODT group after two years (p < 0.003), with no significant change in the DBS þ ODT group. Conclusions: DBS þ ODT in early PD may reduce the risk of clinically important worsening. These findings further confirm the need to determine if DBS þ ODT is superior to medical therapy for managing symptoms, reducing the complications of medications, and improving quality of life. The FDA has approved the conduct of a large-scale, pivotal clinical trial of DBS in early stage PD. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Deep brain stimulation Subthalamic nucleus
1. Introduction After completing a prospective, single-blind pilot trial of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in very early stage Parkinson's disease (PD) [1], Vanderbilt University received FDA approval to conduct a prospective, double-blind, placebo-controlled, pivotal, multicenter, phase III, clinical trial evaluating safety and efficacy of DBS early PD. Experience and data from the pilot study were used to inform the design and endpoints of the pivotal trial. Pre-submission meetings with staff at both the
* Corresponding author. E-mail address: [email protected] (M.L. Hacker). http://dx.doi.org/10.1016/j.parkreldis.2015.08.008 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
NIH and the FDA resulted in recommendations to refocus the pivotal trial with a primary endpoint that would be clinically meaningful to patients considering early DBS therapy. We therefore established a patient-centered composite outcome evaluating two important features of early PD: motor symptoms and complications of medical therapy. Minimum clinically important differences for the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor examination) and Part IV (complications of medical therapy) are 2.3e2.7 and 0.7, respectively [2,3]. These reported differences on components of this validated PD measure [4,5] were used to inform the decision to establish a per-patient change over two years that would be clinically meaningful. An individual subject's clinically important worsening is defined as both a 3 point increase in
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UPDRS Part III ON and a 1 point increase on Part IV. Here, we report analysis of the DBS in early PD pilot using this composite outcome to evaluate the risk of clinically important worsening on measures meaningful to both patients and physicians weighing early DBS implantation. Additionally, results of the primary analysis of the DBS in early PD pilot showed that scores on Part IV diverge between the groups at 24 months, with the DBS plus optimal drug therapy (DBS þ ODT) group relatively unchanged from baseline (þ0.30) while the optimal drug therapy (ODT) control group worsened by two-fold (þ1.9 points) [1]. Complications of medical therapy become increasingly disabling as PD progresses [6], and stabilization of Part IV scores after two years of stimulation in early PD suggests this outcome may be an appropriate endpoint for a pivotal trial. During the design of the phase III clinical trial, members of a CTSAsupported studio raised concerns that enrolling subjects on medication for less than one year may include early PD subjects who would complete the two-year study period before ever being at risk for developing dyskinesias or other motor complications. Similar concerns were expressed by Ahlskog and colleagues [7], who comment that including patients “prior to when motor complications would be expected” would “underestimate frequencies” of motor fluctuations and dyskinesias. A future efficacy trial evaluating Part IV that includes PD patients on medication less than one year could be negatively impacted by a floor effect of this assessment of the complications of medical therapy. Members of the studio suggested that enrolling subjects on medication 1e4 years would better focus the study population on the currently available clinical measures and also have the added benefit of potentially decreasing the likelihood of enrolling participants who would later prove to not have idiopathic PD. We therefore conducted a post hoc analysis of the pilot study of DBS in early stage PD to evaluate outcomes in a more focused study population to provide the data needed to select appropriate endpoints and power the future pivotal, phase III safety and efficacy clinical trial. 2. Methods A prospective, single-blind, randomized, parallel-group, placebo-controlled pilot trial of DBS in early PD (NCT#00282152) that was approved by the FDA (IDE#G050016) and the Vanderbilt University IRB (IRB#040797) completed in 2012 [1]. The pilot study enrolled idiopathic PD patients, age 50e75, Hoehn & Yahr Stage II OFF medication, taking PD medications for 6 months to 4 years at enrollment, without any history of dyskinesias or other motor fluctuations. Here, we conducted a patient-centered outcomes analysis for all subjects with baseline and 24 month UPDRS Part III and IV scores (n ¼ 28) and also for the recommended focused cohort of subjects with medication duration of 1e4 years at enrollment (n ¼ 20). Continuous outcomes were also analyzed for subjects in this focused cohort and compared to published outcomes for the DBS in early PD pilot trial [1]. Pilot study randomization occurred independent of PD medication duration, and therefore, the randomization of subjects in the subset analysis is not compromised by the use of a more focused medication duration. 2.1. Design Detailed descriptions of the study design, enrollment experience, baseline characteristics, and surgical methods for the DBS in early PD pilot trial are published elsewhere [8e12]. Briefly, the pilot trial enrolled early stage idiopathic PD patients, age 50e75, without dyskinesias or other motor fluctuations who provided written informed consent. Subjects who passed screening were admitted
into the Clinical Research Center (CRC) for an eight-day evaluation. On day one in the ON therapy state, a series of PD measures were collected including the Total UPDRS (with Part III videotaped). Subjects' PD medication regimens were also recorded and converted to levodopa equivalents [13], and a battery of neuropsychological tests (including the Parkinson's disease questionnaire39 (PDQ-39) quality of life assessment) was administered. After a seven-day washout (day 8), a subset of measures from day one were collected again in the OFF therapy state (including videotaped Part III). Subjects were then randomized to receive either DBS þ ODT or ODT. Participants randomized to receive DBS þ ODT underwent bilateral STN DBS surgery [9,12]. All subjects returned to the CRC for the same week-long therapy washout every six months during the two-year study period, and the neuropsychological battery was administered annually. 2.2. Statistical analysis Relative risk reductions (DBS þ ODT vs ODT) in the rates of clinically important composite worsening of both PD motor symptoms and complications of medical therapy are expressed as RRR ¼ 100 (1rDBSþODT/rODT), where rDBSþODT and rODT are the rates of composite PD worsening in the DBS þ ODT and ODT groups, respectively. Values of RRR between 0 and 100% favor the DBS group. The RRRs, 95% confidence limits, and P-values were calculated using Stata 13 Software for comparison of incidence rates (IR command) in 2 2 tables using ManteleHaenzel methods. Continuous outcomes were summarized using mean and standard deviation at baseline, 6 month, 12 month, 18 month and 24 month for DBS þ ODT and ODT groups. The changes for the two groups as well as the group difference in changes between each time point from baseline were estimated using mixed effects models that included group effect, time effect (as a factor) and group by time interaction while accounting for the correlations within subject. Parameter estimate, 95% confidence interval and p value were provided. All analyses were implemented using R 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). A significance level of 0.05 was used for statistical inference. 3. Results We conducted a patient-centered outcomes analysis on all subjects from the pilot study and also on the focused cohort on medication 1e4 years at enrollment (Table 1). When data from all subjects in the pilot trial were evaluated, 54% of the ODT group and only 27% of the DBS þ ODT group experienced clinically important worsening after two years. This difference translates to a 50% relative risk reduction for the DBS þ ODT group compared to the ODT group (P ¼ 0.25). Furthermore, when this method was applied to the focused cohort of subjects in the DBS in early PD pilot trial on medication 1e4 years at enrollment, there was an 80% reduction in the risk of clinically important worsening experienced by the DBS þ ODT group compared to the ODT group (P ¼ 0.07). We also analyzed continuous outcomes for the DBS þ ODT and ODT groups in a more focused cohort of subjects from the pilot trial, with a medication duration of 1e4 years. There were no significant differences between the groups at baseline (Table S1), and baseline characteristics for subjects included in this analysis were similar to those from the primary analysis [1]. Outcomes for each group at baseline and 24 months are listed in Table 2. Total UPDRS scores from baseline to 24 months for the ODT group significantly worsened (þ9.68 points; p < 0.003; Table S2), while the DBS þ ODT group scores were unchanged (0.2 points). Change from baseline scores for Total UPDRS was better for the DBS group at every time point (Fig. 1A; p < 0.05 at 24 months).
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Table 1 Relative risk reduction (RRRs) for clinically important worsening in both the motor symptoms and the complications of medical therapy for PD. PD medication duration at enrollment 6 monthse4 years (n ¼ 28a)
Treatment assignment
(1) Clinically worse motor symptoms: 3 increase in UPDRS Part III on
(2) Clinically worse complications of medical therapy: 1 increase in UPDRS Part IV
(3) Composite worsening of PD: both (1) and (2)
ODT (n ¼ 13a) DBS þ ODT (n ¼ 15)
54% 47%
85% 47%
54% 27%
Relative risk reductions in composite clinical worsening (DBS þ ODT vs ODT)
50% 95% CI 0.19e1.32 P ¼ 0.25 1e4 years (n ¼ 20) ODT (n ¼ 11) DBS þ ODT (n ¼ 9)
55% 33%
82% 44%
55% 11% 80% 95% CI 0.03e1.40 P ¼ 0.07
a
Baseline UPDRS Part III On score missing for 1 ODT subject who was excluded from this analysis.
DBS þ ODT group Part III ON scores were improved from baseline at each time point, and after two years of treatment, these motor scores were 3.8 points better in the DBS þ ODT group and 4.1 points worse in the ODT group (Fig. 1B). Part III ON change from baseline scores favored the DBS þ ODT group at each six month evaluation (p < 0.03 at 6, 12, and 24 months). The ODT group scores on Part IV increased by 1.8 at 24 months (p < 0.003; Table S2), with minimal change (þ0.3) in the DBS þ ODT group after two years (Fig. 1C; p > 0.05). Scores on the patient-reported PDQ-39 quality of life assessment significantly declined in the ODT group after 24 months (þ11.5 points; p < 0.001; Table S2), and a between-group comparison revealed that the ODT group worsened by an average of 6.1 points more than the DBS þ ODT group at 24 months (Fig. 1D). Additionally, the DBS þ ODT group was significantly better than the ODT group on change scores at 24 months on the PDQ-39 dimensions of emotional well-being and stigma (p < 0.05). Fig. 2 illustrates the between-group differences in mean change scores at 24 months on the Total UPDRS, PDQ-39 Summary Index, and their respective subscores for subjects on medication 6 months to 4 years [1] and the subset on medication 1e4 years (Table 2). As reported in the primary analysis of all subjects in the DBS in early PD pilot study [1], Total UPDRS, UPDRS Part III ON and OFF, UPDRS Part II OFF, and UPDRS Part IV scores for the DBS þ ODT group were better than the ODT group after two years (orange line, Fig. 2A). These between-group differences are more pronounced when the study population is focused to subjects on PD medications 1e4 years (blue line, Fig. 2A). Similarly, trends observed in analysis of dimensions of the PDQ-39 quality of life assessment are amplified when the inclusion criteria are focused to subjects on medications 1e4 years (Fig. 2B). Furthermore, four out of five PDQ-39 subscores that are highly influenced by motor aspects of PD (activities of daily living, emotional wellbeing, stigma, and bodily discomfort [14]) are each more than 8 points better in the DBS þ ODT group after two years in the present analysis.
4. Discussion Our analysis of a patient-centered outcome evaluating motor features combined with complications of medical therapy suggests that early stage PD subjects treated with medications alone are 2e5 times more likely to experience clinically important worsening than subjects treated with DBS þ ODT (Table 1). Focusing the
inclusion criteria on early PD subjects with a medication duration of 1e4 years revealed a particularly striking 80% reduction in the relative risk of symptom worsening for the DBS þ ODT group. DBS therapy is well-known to improve motor symptoms and reduce the complications of medical therapy in advanced stage PD, and these benefits of DBS þ ODT over ODT were also seen in mid-stage PD [15]. The reduction in the relative risk of clinically important worsening on motor symptoms and complications of medical therapy observed in analysis of the pilot trial of DBS in early PD is consistent with the well-documented superiority of DBS þ ODT over ODT in PD stages that have been tested thus far. Additionally, comparing continuous outcomes from the pilot trial for all subjects and the subset on medication 1e4 years demonstrates that focusing the study population accentuates trends previously observed [1]. This comparison suggests that including PD patients on medication less than one year may have muted between-group differences (Fig. 2). These results suggest that focusing the study population in early stage PD moved scores into meaningful ranges for the wellestablished and validated outcome measures currently used to evaluate PD. Taken together, these analyses support future utilization of this inclusion criterion with this patient-centered composite outcome in trials of DBS in early PD.
4.1. DBS þ ODT is superior to standard medical therapy for the treatment of motor symptoms in early PD Two independent outcomes from this analysis suggest DBS þ ODT is superior to standard care for treating motor symptoms in early PD. First, the changes from baseline in the UPDRS Part III ON scores are better in the DBS þ ODT group than ODT at each time point, with two year change scores improving 15% in the DBS þ ODT group and worsening 19% in the ODT group (Fig. 1B). This assessment, which evaluates the cardinal motor features of PD, was scored by an independent, blinded neurologist in the pilot trial [1] (Fig. 1B). Second, the patient-reported PDQ-39 assessment also favors DBS þ ODT over ODT (Table 2), particularly on dimensions that are highly influenced by motor aspects of PD: activities of daily living, emotional well-being, stigma, and bodily discomfort [14] (Fig. 2B). The superior efficacy of DBS plus medication when compared to ODT for the treatment of motor features of advanced stage PD is well established [16e18]. Criticisms of the ethics of evaluating DBS in early PD frequently center on the assertion that
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Table 2 Baseline and 24 months outcomes. Outcome
DBS þ ODT (n ¼ 9) Baseline
a b c d e f g h i
24 month
Mean difference (95% CI)
Mean difference (95% CI)
Mean difference (95% CI)
P Value
2.18 (0.25) 2.14 (0.23)
0.36 (0.15e0.58) 0.14 (0.02e0.25)
0.14 (0.46e0.19) 0.08 (0.09e0.25)
0.41 0.35
2.22 (6.36e1.92) 2.22 (6.19e1.75)
90 (5.92) 89.09 (5.84)
85.45 (9.61) 85.5 (6.85)
4.55 (8.29e0.80) 3.18 (6.88e0.51)
2.32 (7.9e3.26) 0.96 (6.39e4.47)
0.41 0.73
1.11 (0.08e2.14)
1.77 (1.21)
3.27 (1.9)
1.5 (0.57e2.43)
8.45 (4.93) 10.09 (4.11)
10.73 (6.39) 14.91 (5.2)
2.27 (0.11e4.66) 4.82 (2.14e7.5)
21.09 30.91 2.45 33.77
25.18 41 4.27 43.45
2.17 (0.25) 2.11 (0.22)
0.5 (0.26e0.74) 0.06 (0.07e0.18)
92.78 (4.41) 88.89 (3.33)
90.56 (7.26) 86.67 (7.5)
1.22 (1.3)
2.33 (2.0)
8.89 (4.81) 10.56 (4.48)
11.06 (6.32) 13 (5.96)
26 30.75 1.78 37.89
22.22 39.67 2.11 37.72
(11.65) (11.31) (1.27) (17.4)
24 month
1.82 (0.4) 2 (0.0)
1.67 (0.5) 2.06 (0.17)
(12.22) (10.21) (1.64) (16.39)
Baseline
MIDa
ODT minus DBS þ ODT
2.17 (0.47e4.81) 2.44 (0.52e5.41) 3.78 9.3 0.33 0.17
(8.73e1.17) (4.28e14.32) (0.93e1.6) (6.97e6.63)
(9.89) (8.32) (1.86) (14.14)
(9.63) (9.14) (2.00) (16.49)
4.09 10.09 1.82 9.68
(0.39e8.57) (5.72e14.46) (0.67e2.97) (3.53e15.83)
0.39 (1e1.78)
0.58
0.11 (3.45e3.66) 2.37 (1.63e6.37)
0.95 0.25
2e3c 2e3c
7.87 0.79 1.48 9.85
0.02 0.82 0.09 0.04
2.5e, 5g, 6.2h 2.5e, 5g, 6.2h 0.7f 8d,g
(1.19e14.54) (5.86e7.45) (0.23e3.19) (0.68e19.02)
5.93 (17.8) 17.25 (31.53)
3.26 (8.62) 10.06 (15.67)
2.68 (14.66e9.3) 0.05 (15.02e15.12)
0.0 (0.0) 13.63 (16.12)
4.12 (11.67) 7.14 (14.15)
4.12 (7.15e15.4) 4.25 (18.4e9.89)
64.56 (13.61) 54.44 (14.93)
72 (17.21) 54.33 (25.78)
7.44 (0.58e14.31) 0.11 (8.1e7.93)
67.91 (16) 57.36 (10.33)
69.64 (18.29) 55.82 (21.3)
1.73 (4.48e7.94) 1.55 (8.82e5.72)
5.72 (14.97e3.54) 1.43 (12.27e9.4)
0.23 0.80
65 (11.08) 59.33 (10.11)
68.44 (13.44) 55.89 (10.42)
3.44 (2.48e9.37) 3.44 (9.74e2.85)
63.09 (12.14) 55.36 (12.65)
65.73 (17.38) 55.73 (19.81)
2.64 (2.72e7.99) 0.36 (5.33e6.05)
0.81 (8.79e7.18) 3.81 (4.68e12.29)
0.84 0.38
18.78 (3.27) 21 (4.87) 475.67 (323.09)
18.33 (3.77) 23.12 (5.19) 620.44 (327.25)
19.55 (3.86) 21.09 (3.99) 479.27 (242.72)
18.27 (3.66) 21 (5.66) 596.09 (283.08)
1.27 (3.69e1.15) 0.18 (4.33e3.98) 116.82 (46.63e280.27)
11.94 14.82 11.11 7.64 7.41 11.11 11.11 16.67 11.47
(15.09) (15.61) (8.33) (13.18) (16.37) (7.51) (9.32) (13.82) (7.76)
23.33 19.44 10.64 8.33 6.48 22.22 22.21 21.3 16.83
(25.53) (20.94) (7.83) (8.84) (10.02) (18.78) (18.16) (15.09) (11.37)
MID ¼ Minimally Important Difference. Excludes rigidity. UPDRS Total reported as the sum of UPDRS Parts I, II, III, and IV. UPDRS Total reported as the sum of UPDRS Parts I, II, and III. Ref. [2]. Ref. [3]. Ref. [20]. Ref. [21]. Ref. [25].
0.44 (3.12e2.23) 2.84 (1.79e7.47) 144.78 (35.92e325.48)
11.39 4.63 0.47 0.69 0.92 11.11 11.1 4.63 5.36
(0.04e22.74) (7.73e16.98) (8.6e7.67) (7.91e9.3) (8.48e6.63) (0.18e22.04) (0.3e21.9) (6.99e16.25) (0.49e11.2)
11.82 17.04 14.01 14.77 3.79 20.45 9.85 22.73 14.31
(15.81) (17.33) (13.34) (20.01) (5.73) (13.72) (6.26) (15.41) (9.5)
22.27 30.68 26.89 28.41 8.33 27.27 27.27 35.6 25.82
(25.6) (29.24) (23.23) (27.58) (12.91) (17.06) (22.7) (21.44) (18.55)
10.45 13.63 12.88 13.64 4.55 6.82 17.43 12.87 11.51
(0.19e20.72) (2.46e24.81) (5.52e20.24) (5.86e21.42) (2.29e11.38) (3.07e16.71) (7.66e27.19) (2.36e23.39) (6.22e16.8)
6.8 (9.65e23.25) 4.3 (24.97e16.37)
0.83 (4.43e2.78) 3.02 (9.24e3.2) 27.96 (271.61e215.69)
0.93 9.01 13.35 12.94 5.47 4.29 6.32 8.24 6.15
(16.24e14.37) (7.66e25.67) (2.38e24.31) (1.34e24.54) (4.72e15.66) (19.04e10.45) (8.24e20.88) (7.42e23.91) (1.73e14.04)
0.42 0.68
0.65 0.34 0.82
0.91 0.29 0.02 0.03 0.29 0.57 0.40 0.30 0.13
3.2i 4.4i 4.2i 5.6i 11.4i 1.8i 4.2i 2.1i 1.6i
M.L. Hacker et al. / Parkinsonism and Related Disorders 21 (2015) 1177e1183
Hoehn & Yahr ON OFF Schwab & England ON OFF UPDRS I II “ON” medication “OFF” medication IIIb ON OFF IV Totalc ON/OFF Diaries ON with dyskinesias OFF Finger taps Dominant hand ON OFF Non-dominant nand ON OFF Stand-walk-sit (s) ON OFF Levodopa equivalents (mg) Quality of life PDQ-39 Mobility Activities of daily living Emotion well being Stigma Social support Cognition Communication Bodily discomfort Single index
ODT (n ¼ 11)
M.L. Hacker et al. / Parkinsonism and Related Disorders 21 (2015) 1177e1183
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Fig. 1. Change from baseline scores on Total UPDRS, UPDRS Part III ON, UPDRS Part IV, and PDQ-39 Summary Index. Mean change (D) from baseline scores (SEM) on key PD measures over the two year pilot study period: (A) Total UPDRS, (B) UPDRS Part III ON (motor examination; excluded rigidity), (C) UPDRS Part IV (complications of medical therapy), (D) PDQ-39 (quality of life). z within-group comparison p < 0.03, * between-group comparison p < 0.04 (Table S2).
Fig. 2. Trends observed in analysis of all subjects from the DBS in early PD pilot study are amplified by focusing the inclusion criteria. Spider diagrams show change from baseline to 24 month scores (ODT minus DBS þ ODT) on (A) the UPDRS and (B) the PDQ-39 and their respective subscores from analysis of all subjects in the pilot study (orange lines; [1]) and the present analysis (blue lines; Table 1). The DBS þ ODT group scores are better than ODT for domains with positive values (gray), and the ODT are better than DBS þ ODT for domains with negative values (red). Green PDQ-39 subscores are highly influenced by motor aspects of PD [14].
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early stage PD symptoms are adequately managed by medical therapy and that the potential for DBS-mediated improvements is outweighed by the risks associated with surgery. The combination of blinded clinician-rated and patient-reported outcome measures demonstrating DBS þ ODT is superior to ODT offers strong evidence that there is considerable room for improvement in treatment options for early stage PD. 4.2. Limitations Although data from the pilot study of DBS in early stage PD were prospectively collected [1], this analysis is limited by its use of post hoc comparisons. Another limitation of this dataset is its small sample size. However, this sample size reduction did not increase the variability of the data (Table 2) compared to the primary analysis [1], which suggests this analysis was conducted on a more homogenous sample of early stage PD subjects. Although the assessments used in the pilot study are well established, validated outcome measures for Parkinson's disease, potential floor effects may restrict their utility in very early stage PD. Additionally, the pilot trial was open-label for all measures except for a single-blind assessment of UPDRS Part III, and outcomes reported may have been influenced by knowledge of treatment assignment through placebo or lessebo effects [19]. The pivotal trial design approved by the FDA addresses this concern by making the best attempt at conducting double-blind study. STN-DBS therapy for advanced PD significantly improves motor symptoms and quality of life while reducing medication requirements [16e18]. Analysis of all subjects from the DBS in early PD pilot trial showed less medication utilization in the DBS þ ODT group compared to ODT [1]. However, this reduced medication requirement with DBS þ ODT versus ODT was not observed in the analysis of the focused cohort (Table 2). The small sample size of the focused analysis may have precluded detection of the expected medication reduction (n ¼ 20). The role STN-DBS plays on reducing the medication burden of early stage PD will be evaluated in the large-scale, phase III, pivotal trial. 4.3. Meaningful differences on PD outcome measures This analysis offers preliminary data to inform the design of a large, multicenter study evaluating safety and efficacy of DBS þ ODT in early stage PD. By focusing the study population on subjects with medication duration of 1e4 years, this analysis shows that clinically meaningful differences on established PD outcome measures could be achieved in early stage PD. The improvement of DBS þ ODT over ODT on the change in UPDRS motor score (Part III) in this analysis was statistically significant at 6, 12, and 24 months (p < 0.02; Table S2). The between-group difference in the change scores on this blinded, clinician-rated measure was 7.9 points, which well exceeds minimal clinically important changes reported for UPDRS Part III [2,20,21] (Table 2). The ODT group experienced a significant worsening of UPDRS Part IV (complications of medical therapy) after 24 months (p < 0.003), with a minimal change in the DBS þ ODT group after two years (p ¼ 0.63). This between-group difference for the change from baseline to 24 months of 1.5 is twice the reported minimal important change for Part IV (Table 2) [3]. Although some PD medications, such as amantadine [22,23] or memantine [24], are suggested to diminish motor fluctuations, these medications were not used to treat a sufficient number of subjects over the two year-study period to impact the results (one ODT subject was treated with amantadine). Although the PDQ-39 quality of life summary index scores increased for both groups after two years, the ODT group experienced significant worsening from baseline to 24 months (Fig. 1D;
p < 0.001) with minimal change in the DBS þ ODT group from months 12e24. A minimal important difference for the PDQ-39 summary index is reported to be 1.6 [25], and the between-group difference on the 24 month change scores was better in the DBS þ ODT group by more than three times this reported minimal difference. Subanalysis of PDQ-39 reveals that the difference in the summary index scores is largely driven by the domains of activities of daily living, emotional well-being, stigma, and bodily discomfort/ pain (Fig. 2; Table 2). Between-group differences on each of these dimensions favored the DBS þ ODT group by more than 8 points and exceeded minimal important differences from two-to four-fold (Table 2) [25]. Of note, between-group cognition scores on the PDQ-39 favored ODT over DBS þ ODT by a minimal important difference (Table 2) [25]. Neuropsychological and cognitive decline is an established consequence of PD [26], and concerns exist related to DBS in limited domains [27,28]. A detailed neuropsychological analysis of the DBS in early PD cohort is reported elsewhere [29]. Recent evidence suggests that the surgical procedure, not active stimulation, may be responsible for a limited cognitive decline if present [30]. The double-blind design of the pivotal trial approved by the FDA will allow for a direct comparison of the effect of surgery versus STN stimulation to further enlighten the source of the cognitive impairment in PD patients treated with DBS þ ODT. These results suggest that DBS in early PD reduces the relative risk of clinically important worsening and is superior to medication alone for treating motor symptoms, reducing the complications of medical therapy, and providing better quality of life. Additional study is need to confirm these findings, and the FDA has approved this focused inclusion criteria and patient-centered outcome in a prospective, pivotal, phase III, multicenter, double-blind, placebocontrolled clinical trial designed to definitively discern whether DBS is superior to medication alone in early PD. Acknowledgments We thank our study coordinator, Odessa Lankford, for her dedication and commitment to the trial. Research reported in this publication was supported by Medtronic, Inc., by Vanderbilt CTSA grant UL1TR000445 from the National Center for Advancing Translational Sciences (NCATS), by NCATS/NIH award UL1TR000011, by NIH R01 EB006136, by private donations and by The Michael J. Fox Foundation for Parkinson's Research. Medtronic representatives did not take part in data collection, management, analysis, or interpretation of the data or in preparation, review, or approval of the manuscript. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2015.08.008. References [1] D. Charles, P.E. Konrad, J.S. Neimat, A.L. Molinari, M.G. Tramontana, S.G. Finder, C.E. Gill, M.J. Bliton, C. Kao, F.T. Phibbs, Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease, Parkinsonism Relat. Disord. 20 (2014) 731e737. [2] L.M. Shulman, A.L. Gruber-Baldini, K.E. Anderson, P.S. Fishman, S.G. Reich, W.J. Weiner, The clinically important difference on the Unified Parkinson's Disease Rating Scale, Arch. Neurol. 67 (2010) 64e70. [3] H. Honig, A. Antonini, P. Martinez-Martin, I. Forgacs, G.C. Faye, T. Fox, K. Fox, F. Mancini, M. Canesi, P. Odin, Intrajejunal levodopa infusion in Parkinson's disease: a pilot multicenter study of effects on nonmotor symptoms and quality of life, Mov. Disord. 24 (2009) 1468e1474. [4] P. Martinez-Martin, A. Gil-Nagel, L.M. Gracia, J.B. Gomez, J. Martinez-Sarries, F. Bermejo, Unified Parkinson's Disease Rating Scale characteristics and structure. The cooperative multicentric group, Mov. Disord. 9 (1994) 76e83.
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