Abstract
The FDA has approved a multicenter, double-blind, Phase III, pivotal trial testing deep brain stimulation (DBS) in 280 people with very early stage Parkinson’s disease (PD; IDE#G050016). In partnership with The Michael J. Fox Foundation for Parkinson’s Research, we conducted a survey to investigate motivating factors, barriers, and gender differences among potentially eligible patients for participation in a trial testing DBS in early PD compared to standard medical treatment. The majority of survey respondents (72%) indicated they would consider learning more about participating. Early PD patients are therefore likely to consider enrolling in trials of invasive therapies that may slow symptom progression and help future patients.
INTRODUCTION
Vanderbilt University completed a prospective, randomized, controlled, single-blind pilot clinical trial evaluating safety and tolerability of subthalamic nucleus deep brain stimulation (DBS) for early Parkinson’s disease (PD; clinicaltrials.gov NCT00282152) [1–3]. Thirty subjects were randomized to optimal drug therapy (ODT) or DBS plus ODT. The pilot met its primary safety endpoint [1], and preliminary data from the pilot trial suggest DBS in early PD may reduce the relative risk of worsening for motor symptoms and complications of medical therapy compared to medication alone by 50–80% [4]. Based on the pilot trial results, the FDA has approved the conduct of a multicenter, double-blind, pivotal trial testing DBS in 280 people with early PD (IDE#G050016).
Promising clinical trials are often hampered by inadequate recruitment [5]. Although recruitment and retention in the single-center pilot trial of DBS in early PD were outstanding (100% and 97%, respectively), additional information is needed to understand how larger cohorts of patients with early PD view a trial testing an invasive therapy compared to standard pharmacological intervention. Numerous factors with the potential to influence patient perceptions of clinical trials have been previously identified, including expectation of benefit, desire to help future patients, and risks associated with an experimental therapy [6–16]. However, the importance of these factors to early PD patients is unclear. To address these knowledge gaps, we partnered with The Michael J. Fox Foundation for Parkinson’s Research (MJFF) to conduct a survey investigating motivating factors, barriers, and gender differences for participation in a trial testing DBS in veryearly PD.
METHODS
Fox Insight is a longitudinal, virtual, patient-centered observational study led by MJFF (https://foxinsight.michaeljfox.org/). Our collaboration represents the first external survey hosted by Fox Insight. An invitation to complete the IRB-approved survey (New England IRB#14-236) was sent via email to 469 Fox Insight participants who met basic inclusion criteria for the FDA-approved pivotal trial: age 50–70, disease duration <4 years, without dyskinesias or other motor fluctuations. The survey was available on Fox Insight February 3–15, 2016.
Survey respondents read a passage describing A) the DBS surgical procedure and associated risks, B) results from the pilot trial suggesting DBS in early disease may slow the rate of symptom worsening, and C) a double-blind clinical trial testing DBS in early PD in which all subjects undergo DBS surgery and 1 : 1 randomization to active or inactive stimulation for a two-year blinded phase, followed by a two-year open-label phase in which all subjects receive active stimulation. Participants who agreed to take the survey then answered “yes” or “no” to whether they would consider learning more about participating in a trial like this one and described the most important reason(s) for their decision in free text responses. Next, participants individually rated on five-point Likert-type scales the importance of various motivating factors and barriers [6, 16] for considering whether to learn more about participation in a trial like the one described. Finally, participants were asked how likely they would be to withdraw from the trial during the blindedphase.
Free text responses were categorized and tabulated according to theme (e.g., disease modification, helping research). Ratings were grouped at each extreme of importance (i.e., not at all/slightly, moderately, very/extremely). All available data were analyzed (<2% missing for any rating).
RESULTS
Participants
The survey was completed by 158 early PD patients (34% response rate) who met basic inclusion criteria for the pivotal trial (Table 1). Demographic characteristics between male and female respondents were similar.
Recruitment and retention feasibility for a future trial of DBS in early PD
After reading the passage, 72% of participants indicated they would consider learning more about participating in the trial. Of these, 75% indicated they would be unlikely to withdraw early from a double-blind DBS trial, and only 29% expressed concern about not knowing whether the device is on or off during the double-blind phase. Eighty-two percent did not express concern about undergoing weeklong washouts of PD medication and stimulation. Importantly, 41% of these very early stage PD participants felt their symptoms were not adequately controlled with medications.
Free text responses
Of the “yes” respondents (n = 114), the most commonly cited free text response reasons for interest in the trial were desire to help research and/or other PD patients (48%), and 45% mentioned the possibility of disease modification or slowing progression of PD. Of the “no” respondents (n = 44), 56% listed wanting to avoid DBS surgery. Additionally, 41% of “no” respondents perceived the risk-benefit ratio to be unfavorable, and 30% indicated satisfactory control of PD symptoms as a major factor discouraging participation. Eleven percent of “no” respondents were concerned about the possibility of being randomized to inactive DBS.
Motivating factor and barrier ratings
Respondents then independently rated the importance of thirteen motivating factors and fifteen barriers that were presented (Table 2). The most important motivating factor was possible slowing of PD symptom worsening, and the least important motivating factor was race/ethnicity of the research team. The most important barrier was fear that participating could worsen one’s health, and the least important barrier was previous negative experiences with clinical research.
Gender differences
Proportions of men and women who indicated they would consider learning more about participating in the trial were similar (68%, 51/75 and 76%, 63/83, respectively). Men and women rated the importance of both potential benefits and risks of participation in the trial similarly (Table 2). However, more than twice as many women as men placed high importance on “Having your hair shaved for the DBSsurgery.”
DISCUSSION
This inaugural collaborative Fox Insight survey was conducted to explore motivating factors and barriers for participation in an FDA-approved, double-blind trial of DBS in early PD. A majority of respondents expressed interest in learning more about becoming a participant, and this enthusiastic response supports feasibility of recruitment for the DBS in Early PD pivotal trial. Additionally, 75% of “yes” respondents indicated they would not be likely to withdraw from the trial early. Notably, nearly half of respondents who expressed interest in the trial indicated inadequate PD symptom control, demonstrating the need to investigate new treatments for early PD.
Women are underrepresented among DBS recipients [9, 17], and although this discrepancy is well-documented, its origin is unclear. Women may be less inclined to undergo DBS surgery than men. Alternatively, PD may progress (or appear to progress) differently in men and women [18], making men more likely candidates for DBS under the current indication. Investigating DBS for earlier stages of PD could change this paradigm if the results of the DBS in Early PD pivotal trial are positive. Therefore, it is important to investigate differences in how men and women perceive DBS and related clinical research.
Despite efforts to include women in the pilot trial, only 3/30 subjects randomized were female [2]. Women who were initially interested in the trial often cited risks of DBS surgery and cosmetic concerns as major barriers. However, in this survey, gender did not appear to influence expression of interest in the trial or the importance placed on risks associated with DBS surgery. A possible association between female gender and higher importance placed on hair shaving was identified (Table 2). Efforts to overcome this barrier, such as offering compensation toward the cost of wigs, should be implemented in future DBS clinical trials.
PD is a relentlessly progressive condition with no known cure, which makes therapeutic misconception a particular concern for clinical trials in this population [16, 19]. Survey participants placed high importance on helping research/future PD patients and possible disease modification when considering learning more about trial participation. PD patients in the pilot and other studies identified both altruism and the possibility of personal benefit as highly motivating for participation in research [6, 19]. Such findings highlight the need for comprehensive informed consent procedures in future PD clinical trials. The pilot trial’s three-step expanded informed consent process likely contributed to the excellent retention rate [2, 13], and the same procedure will be implemented in the FDA-approved pivotal trial.
This study has several inherent limitations. Although there is insufficient racial/ethnic diversity in this study, the proportion of minority respondents in this survey is similar to minority representation among Fox Insight participants. As participants in a long-term observational study, the Fox Insight cohort constitutes a relatively small group of highly engaged patients who may be more likely to show interest in clinical research than members of the greater PD community. Nevertheless, Fox Insight participants represent candidates who would be screened for clinical trials.
Findings from this collaborative effort with MJFF suggest gender differences persist among PD patients considering DBS therapy. Women may assign higher importance to cosmetic concerns when considering participation in DBS clinical trials. Additionally, greater emphasis should be placed on engaging minority populations in PD clinical research.
Results of this patient survey indicate people with early PD are likely to consider enrolling in trials of invasive therapies that may slow symptom progression and help future patients. Furthermore, enrolled subjects are unlikely to withdraw from such studies. These findings support the likelihood of successful recruitment and retention in the FDA-approved DBS in Early PD pivotal trial.
CONFLICT OF INTEREST
Vanderbilt University receives income from grants and contracts with Allergan, Ipsen, Lundbeck, Merz, Medtronic, and USWorldMeds for research or educational programs led by David Charles. David Charles receives income from Allergan, AstraZeneca, Ipsen, and Medtronic for consulting services. There are no financial disclosures for Lauren Heusinkveld, Mallory Hacker, Maxim Turchan, Madelyn Bollig, Christina Tamargo, William Fisher, Lauren McLaughlin, and Adria Martig.
Footnotes
ACKNOWLEDGMENTS
This work has been supported by The Michael J. Fox Foundation for Parkinson’s Research.