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DOMINANTLY INHERITED ALZHEIMER NETWORK TRIALS UNIT (DIAN-TU): TRIAL SATISFACTION AND ATTITUDES TOWARDS FUTURE CLINICAL TRIALS

 

H. Liu1, J. Li2, E. Ziegemeier1, S. Adams1, E. McDade1, D.B. Clifford1, Y. Cao3, G. Wang3, Y. Li1,3, S.L. Mills1, A.M. Santacruz2, S. Belyew1, J.D. Grill4, B.J. Snider1, C.J. Mummery5, G. Surti6, D. Hannequin7, D. Wallon7, S.B. Berman8, I.Z. Jimenez-Velazquez9, E.D. Roberson10, C.H. van Dyck11, L.S. Honig12, R. Sanchez-Valle13, W.S. Brooks14, S. Gauthier15, D. Galasko16, C.L. Masters17, J. Brosch18, G.-Y.R. Hsiung19, S. Jayadev20, M. Formaglio21, M. Masellis22, R. Clarnette23, J. Pariente24, B. Dubois25, F. Pasquier26, R.J. Bateman1, J.J. Llibre-Guerra1, for the DIAN-TU Study Team

 

1. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA; 2. Department of Medicine, University of Missouri, Columbia, MO, USA; 3. Division of Biostatistics, Washington University in St Louis, St Louis, MO, USA; 4. Departments of Psychiatry & Human Behavior and Neurobiology & Behavior at the University of California, Irvine, USA; 5. University College of London, London, England; 6. Brown University, Providence, RI, USA; 7. Centre Hospitalier Universitaire de Rouen, Rouen, France; 8. University of Pittsburgh, Pittsburgh, PA, USA; 9. University of Puerto Rico School of Medicine, San Juan, PR, USA; 10. University of Alabama at Birmingham, Birmingham, AL, USA; 11. Yale University School of Medicine, New Haven, CT, USA; 12. Columbia University Irving Medical Center, New York, NY, USA; 13. Hospital Clínic i Provincial de Barcelona, IDIBAPS-Universitat de Barcelona, Barcelona, Spain; 14. Neuroscience Research Australia and University of New South Wales Medicine, New South Wales, Australia; 15. McGill University Research Center for Studies in Aging, Montreal, Canada; 16. University of California, San Diego, CA, USA; 17. The Florey Institute, University of Melbourne, Melbourne, Australia; 18. Indiana University School of Medicine, Indianapolis, IN, USA; 19. University of British Columbia, Vancouver, Canada; 20. University of Washington School of Medicine, Seattle, WA, USA; 21. Neurological Hospital, Centre Hospitalier Universitaire de Lyon, Bron, France; 22. Sunnybrook Research Institute, Toronto, Canada; 23. Australian Alzheimer’s Research Foundation, University of Western Australia, Perth, Australia; 24. Centre Hospitalier Universitaire de Toulouse, Toulouse, France; 25. Neurological Institute of the Salpetriere, University Hospital, Paris, France; 26. Centre Hospitalier Régional Universitaire de Lille, Lille, France

Corresponding Author: Jorge J Llibre Guerra, 4488 Forest Park 00328, T: 314.273-5439, St. Louis MO 63108, USA, jllibre-guerra@wustl.edu; Haiyan Liu, 4488 Forest Park 00328, T: 314.273-5819, St. Louis MO 63108, USA, haiyanliu@wustl.edu

J Prev Alz Dis 2024;
Published online March 19, 2024, http://dx.doi.org/10.14283/jpad.2024.61

 


Abstract

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU).
METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants’ clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials.
RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial’s demographic distribution. Participants’ decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome.
CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

Key words: Dominantly Inherited Alzheimer’s Disease (DIAD), Dominantly Inherited Alzheimer Network-Trial Unit (DIAN-TU), Alzheimer’s Disease (AD), Clinical trial satisfaction, Home Health Nursing (HHN).


 

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) aggregations and neurofilament tau tangles, leading to a progressive decline in cognitive functions and activities of daily life. Approximately 6.2 million Americans are currently living with AD dementia (1, 2). AD has been recognized as one of the most financially burdensome diseases in the United States. Delaying the onset of AD results in substantial savings, as a one-year delay in disease onset would save $70 billion in 2030, while a five-year delay might save a total cost by $599 billion by 2050 (3, 4, 5, 6).
Clinical trials pave the way for advancements in medicine and involve a collaboration of various stakeholders, from sponsors and investigators to participants and regulators. The infrastructure supporting these trials requires time, funding, skilled personnel, supplies, robust support systems, and a clear roadmap. Yet, they face challenges like a reduced workforce, complex regulatory requirements, and issues in participant recruitment and retention (7). Challenges to conducting AD clinical trials include the slow rate of recruitment, heterogeneity of the AD patient population, and operational complexities, among others (8, 9, 10). The use of adaptive trial platforms, combined with the existence of AD trial-ready cohorts, is thought to improve AD trial development and efficiency (8).
Participant satisfaction is a relevant measurement of clinical trials, especially for trial platforms and cohort-ready populations. However, participants’ satisfaction in clinical trials is understudied; therefore, little is known about the factors that influence trial satisfaction. Several aspects may influence participant satisfaction in clinical trials, including knowledge about trial procedures, participant incentives for study enrollment, and trial-related burden (10, 11). In an era of increasing numbers of trials in AD and longer and more complex trials, participants’ experiences need to be explored in order to better understand alternatives to boost participant recruitment and reduce trial drop out (12).
In 2012, the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) launched the first adaptive prevention trial in dominantly inherited Alzheimer’s disease (DIAD). The DIAN-TU adaptive prevention study was conceived using a platform designed to allow the simultaneous testing of treatments from multiple industry partners. This design enables trial efficiencies by using shared placebo groups, a unified protocol, and a single Investigational New Drug, eliminating the need for multiple regulatory submissions for the drug. Results from the first two drugs implemented in the platform, gantenerumab (an anti-fibrillar Aβ antibody) and solanezumab (an anti-soluble Aβ antibody), were published in 2021 (13). As the DIAN-TU trial platform continued, the study implemented a run-in period during which data from cognitive measures and tau PET studies were collected in preparation for launching three tau next-generation (NexGen) drug arms (14) In addition, a primary prevention trial in DIAD participants 11 to 25 years before estimated symptom onset is in the launch preparation stage (15).
A key component for the platform success is participant satisfaction and input for future design. Therefore, a participant satisfaction questionnaire tailored to the DIAN-TU-001 trial was disseminated to: 1) examine research participants’ levels of satisfaction and perceptions towards clinical trials within the DIAN-TU-001 platform and 2) optimize future trial design to increase participation and retention in the platform.

 

Methods

Participants

The design of DIAN-TU-001 clinical trial (NCT01760005) has been previously described (11). In brief, DIAN-TU-001 was a phase II/III randomized, double-blinded, placebo-controlled trial of gantenerumab or solanezumab vs placebo in participants with a family history of DIAD. Eligible participants included known or at-risk DIAD pathogenic family members who were between -15 to +10 years from the expected age of symptom onset (EYO) (16) and had a Clinical Dementia Rating® (CDR®) (17) score of 0 (no cognitive symptoms) to 0.5 (mild cognitive symptoms). Mutation non-carriers were assigned to placebo and not included in efficacy analyses. DIAD mutation carriers were randomized 3:1 (active: placebo). Clinical, cognitive, and biomarker characteristics at baseline have been previously described. The protocol was approved by ethics committees at participating sites, and all participants provided written informed consent. The survey was conducted under the DIAN-TU trial central Institutional Review Board (IRB) for US sites, and local IRBs in Australia, Canada, France, Spain, and the UK. No additional consent was required to complete the survey. At the end of the trial, all DIAN-TU sites trial were encouraged to distribute the trial satisfaction questionnaire to all participants. Participants were contacted via email or phone call. Most sites emailed the survey using a REDCap (Research Electronic Data Capture) link and set up follow-up phone calls. The survey was completed online using REDCap (self-administered or with the assistance of a family member) between April 2020 and August 2021.
To enhance trial participation and alleviate participant inconvenience, the DIAN-TU-001 platform incorporated home-based trial activities facilitated by trained home health research nurses (HHN). This methodological adaptation was geared towards participants residing away from DIAN-TU trial sites, enabling them to receive monthly administrations of the study drug or placebo and other study measures in the comfort of their homes. It is noteworthy that the commitment for participants entailed travel to annual site visits lasting 3-4 days, in addition to frequent (monthly) clinic visits, or home visits by the HHN for drug administration, and multiple visits for safety MRI scans at special scanning sites, throughout the trial’s duration.

Survey development

To create the participant satisfaction survey tailored to the DIAN-TU platform, we reviewed the literature to identify key areas relevant to measuring participant satisfaction in research and clinical trials, followed by a deliberative session to define critical areas to assess trial satisfaction and help future trial design. Several areas of inquiry emerged as key components for the assessment of trial satisfaction and future trial participation including: 1) informed consent process, 2) trial infrastructure, procedures, and visit schedule, 3) reasons for trial participation, 4) use of home health nurse services 5) likelihood of participation in additional trials and 6) Future candidate therapies, combination trials and modes of administration. Also, of interest was whether participants experienced improvements in health care compared to prior participation in the trial. Changes in health care were measured using perceptions before and during trial participation.
The final data collection instrument included 50 questions on a 5-point Likert scale (Strongly Agree, Agree, Neutral, Disagree, Strongly Disagree), five frequency ranking questions (too long, just right, not long enough), nine questions (yes or no) and five multiple selection questions, for a total of 68 questions. Each section included an open-ended text field to capture free-form response data. The survey took approximately 30-45 minutes to complete. The survey was translated into English, French and Spanish to capture all the languages across DIAN-TU sites. The English version of the survey is included in the supplemental material (Appendix 2).
The final version was discussed and approved with DIAN-TU site PIs to ensure cultural validity at each of the DIAN-TU countries and sites. REDCap was used as the platform for implementing the survey and capturing the details of research participants’ experience across the DIAN-TU-001 sites.

Statistical Analysis

The primary analysis population included DIAN-TU-001 participants who were randomized and had at least one site visit baseline and one follow-up assessment. Demographic and baseline characteristics of the participants are summarized as mean ± SD for continuous variables and n (column percentage) for categorical variables. Surveys with missing data were excluded from analyses at the question level only.
Regression analysis was conducted to identify factors affecting satisfaction, accounting for potential confounders like perceived health change during the trial. Analyses were carried out using SAS® software version 9.4 (SAS Institute Inc., Cary, NC, USA), R version 4.3.1(Copyright © 2023 The R Foundation for Statistical Computing), and IBM SPSS Statistics version 29.0 (IBM Corp., Armonk, NY, USA). No correction for multiple comparisons was made; a p-value <0.05 for each independent item was deemed significant.

 

Results

In the DIAN-TU study, which encompassed 24 established sites, a total of 194 participants were enrolled. The study maintained an overall retention rate of approximately 68% (n=131), with a dropout rate of around 32% (n=63). The average yearly retention rate is 92.4% for a dropout rate of 7.6%. The trial retention rate for Mutation Carriers (MC), consider as the trial target population, was 73% and 52% among Non-Carriers (NC). The predominant reason for the high dropout rate among NC was unblinding to mutation status (54.2%, n=24). Among MC, 39 (27%) participants discontinued from the trial. The main reasons for dropouts included: 20 due to disease progression, 6 due to adverse events or meeting protocol discontinuation criteria, 5 due to trial-related burden, and 8 due to other reasons (13).
The DIAN-TU coordinating center requested that study sites distribute the survey to all participants who completed a baseline visit and at least one follow-up assessment. Out of 24 sites, surveys were received from participants enrolled at 15 sites, which represents a population of 108 participants from the DIAN-TU-001 trial. From this subset, 58 valid responses were collected between April 2020 and August 2021, yielding an aggregate response rate of 53.7%. Demographic characteristics of the survey respondents are shown in table 1. In summary, the average age was 48.7 years (SD=8.4) and 32 of the respondents (55.2%) were female. Geographically, most respondents were from North America sites, representing 61.8%, followed by Western Europe at 29.1%, with other regions making up the remaining 9.1%. The mean education level was 15.5 years (SD=3.0), 17.2% had 12 years or less years of education. Overall demographics characteristics of survey responders did not differ from the overall trial population.

Table 1. Demographic and Geographic Profile of DIAN-TU-001 Trial Participants vs. Post-trial Satisfaction Survey Respondents

 

DIAN-TU-001 overall trial satisfaction

In the DIAN-TU-001 trial satisfaction survey, 96.5% (n=56) of the respondents expressed satisfaction with their clinical trial experience. Specifically, 58.6% (n=34) strongly agreed, while 37.9% (n=22) agreed with their overall contentment with the trial. 91.4% of the responders would recommend the trial to family and friends. Furthermore, 96.5% (n=56) affirmed they would make the same decision to enroll in the DIAN-TU-001 trial again. While the majority resonated with positive sentiments, 12.1% (n=7) contemplated discontinuation during the trial, primarily due to the demands of trial activities. A minority of 3.4% (n=2) remained neutral or expressed dissatisfaction with their trial experience. Forty-one participants (70.7%) considered that their overall medical care was enhanced by participating in the DIAN-TU, while seventeen participants (29.3%) experienced no change in care. A significant 84.5% felt pride in their contribution to the DIAN-TU trial. It is worth highlighting that age, gender, or education did not influence these satisfaction levels (p=0.18, 0.12, and 0.30, respectively). See Fig.1 and Table 2.

Table 2. Participant Feedback on Various Aspects of the DIAN-TU-001 Trial Experience

Figure 1. Participants Satisfaction Feedback

Pie charts of participants’ overall evaluation: The central pie chart is the participants’ overall satisfaction (4-level) and the outer layer pie charts are participants’ feedbacks on different aspects of the trial.

 

DIAN-TU-001 personnel and procedures related trial satisfaction

Of the 58 participants, 98.3% (n=57) indicated they were satisfied or very satisfied with the trial personnel and the care provided during the clinical trial. Participant satisfaction with information disclosed on the consent form was high (93.1%, n=54); 6.9% (n=3) felt neutral or thought that the trial’s informed consent did not provide enough information on what to expect during the trial (n=1). In addition, 98.3% (n=57) of the participants considered that information and discussions received before participating in the DIAN-TU-001 trial prepared them for the experience in the trial.
Participants were also asked to rate their satisfaction with the trial effort and related procedures. Baseline and annual visits were conducted at DIAN-TU-001 sites; these visits had an average duration of three to four days to complete all of the assessments and trial procedures. Regarding satisfaction with the time and effort of participating in the trial, the majority of the participants (n=42, 73.7%) considered the length of annual visits as adequate, while 21.0% (n=12) would have preferred shorter and 5.3% (n=3) would have preferred longer visit schedules. Twenty-three participants (39.7%) reported experiencing emotional distress related to trial visit procedures (e.g., lumbar puncture, cognitive testing, neuroimaging studies, reminder of the disease progress etc.). The main reasons for emotional distress related to the trial included: cognitive testing (n=10, 17.2%), lumbar puncture (n=12, 20.7%), the trial being a reminder of the disease process (n=4, 6.9%) and neuroimaging studies (n=6, 10.3%).
Common themes noted in 17 participants’ providing additional comments included high satisfaction with clinical and research staff (11/17, 64.7%), driven by motivations such as aiding Alzheimer’s research (8/17, 47.1%), accessing new medications (1/17, 5.9%), and joining a supportive community (1/17, 5.9%). Participants also expressed occasional grievances with logistical issues (e.g., convenience of scheduling, timing of visits, wait times, travel time) (1/17, 5.9%), and burdens associated with clinical testing (e.g., emotional distress from cognitive testing as the disease progressed, LP side effects, claustrophobia during neuroimaging) (1/17, 5.9%).

Home health nurse (HHN) services

To facilitate trial participation and reduce burden, the DIAN-TU-001 platform introduced the option of home-based trial activities conducted by trained home health nurses. The initiative aimed to allow those not living near a DIAN-TU trial site to receive monthly administration of the study drug or placebo at participants’ residences by a trained home health research nurse, if this service was available in their country. Participants living near a DIAN-TU trial site could receive the monthly drug administration at the site. Participants could opt to receive monthly IP administrations at their host DIAN-TU trial site or in their home via the HHN, if available. In addition to drug administration, HHN were responsible for monitoring participants for adverse events and serious adverse events, capturing vital signs, and other trial-associated tasks. HHN services were approved for use in all countries associated with the DIAN-TU sites. However, not all sites chose to offer this option to their participants. Here we detail the participants’ experiences with HHN among survey respondents enrolled at sites with HHN and who were offered HHN services (n=30/58).
Nineteen out of thirty participants (19/30, 63.3%) chose to have monthly visits conducted by a home health nurse, with 94.7% (n=18) of those indicating a positive and satisfactory experience with the HHN services. Of the eleven who didn’t use the service, two would consider it for future trials, whereas seven would not, and two didn’t respond. In open-ended comments, two participants highlighted the significance of having a nurse who made them feel at ease and was adequately qualified, noting that this enhanced their clinical trial experience. Several participants highlighted a desire to retain their assigned home health nurse for any subsequent trials. Of survey respondents who endorsed not being offered the option of HHN (n=28), if given the option in the future, 78.6% (n=22) would have opted for HHN services for monthly visits (Figure 2).

Figure 2. Evaluations towards home health nurse services

A) This algorithm illustrates the collection of HHN service data, detailing the satisfaction levels of those who utilized HHN and the potential preferences of those who did not. B) This stacked bar chart shows participant responses to HHN services availability with percentage. HHN: Home Health Nursing.

 

Future trial participation, candidate therapies and genetic status awareness

To avoid the requirement of genetic disclosure for participation and thus ensure enrollment goals were met, both non-carriers and carriers who were unaware of their mutation status were allowed to enroll in the trial. Non-carriers were allocated to placebo18,19. Of the 58 respondents, 32 (55.2%) learned their genetic status prior to baseline, 7 (12.1%) during the trial, and the remaining 19 (32.7%) remained blinded until the end of the trial.
With the transition to Gantenerumab Open Label Extension (OLE), participants were required to learn their genetic status to participate in the OLE. Among responders without prior knowledge of their genetic status (n=26), sought counseling through the DIAN-TU genetic counseling and testing (GCT) program and obtained their genetic results, which then guided their choice to participate in the OLE phase of the study.
At trial completion, 77.2% of the survey respondents strongly agreed (n=38) or agreed (n=6) about considering participation in a future trial. The possibility of a negative trial did not affect the willingness to enroll in future trials; 75.4% of the participants strongly agreed (n=32) or agreed (n=11) about future trial participation, even in the case of negative trial results. Finally, in the context of a positive trial result, 91.4% endorsed enrolling in future combination trials in which an effective drug would be offered to all the participants, in addition to randomization to a new investigational drug.

 

Discussion

Findings from our study underscore that a significant majority of respondents felt positive about their experience in the clinical trial. This satisfaction spanned various dimensions, from trial logistics to perceived benefits, highlighting the commendable work of the research team and the efficacy of home health nursing services. These outcomes echo previous literature, which pinpoints quality of care, staff proficiency, and the cohesive organization of trial operations as pivotal determinants of participant contentment in clinical trials (20, 21). However, participants expressed concerns about trial burden, and unsatisfactory clinical outcomes, that will be important to fully understand to improve future trial designs and operations.
In the broader research context, participant satisfaction plays a significant role in shaping the outcomes and overall credibility of clinical trials. For instance, a study by Adler et al. (2020) emphasized that higher levels of satisfaction can directly correlate with better adherence to trial protocols and reduced dropout rates (22). Other research by Tantoy et al., (2021) elucidated that satisfied participants are more likely to engage in future clinical trials, thereby ensuring a continuous pool of willing participants for advancing medical science (20).
Given the robust satisfaction indicators from the first two drug arms of the DIAN-TU trial maintaining and even amplifying efficiencies introduced in the DIAN-TU trial platform will benefit future trials targeting DIAD participants. Not only will this approach likely improve recruitment and retention rates, but it will also foster a more trusting and collaborative environment between researchers and participants, fortifying the foundation for successful clinical trials in the future. Reasons for the observed level of trial satisfaction may include the high commitment of site Principal Investigators (PIs) and personnel to a population with very early onset of dementia and a long family history of the disease. Additionally, the efforts of the DIAN Expanded Registry (DIAN EXR), which engages directly with families and participants worldwide for recruitment, education, and support, likely contribute to this satisfaction. The DIAN EXR hosts webinars, meetings and conferences during which families are encouraged to provide feedback and opinions on trial design and implementation. In addition, several individuals from DIAD families serve as members on the DIAN study steering committee, contributing unique insights from their collective experiences as family members and research participants. Of note, the decision to allow inclusion into the DIAN-TU trial without knowledge of genetic status was a recommendation proposed by DIAN participants during DIAN EXR webinars. DIAD family members serving in the steering committee are key in providing their perspectives and advising on trial design and representing the voices of family members in general.
In our study, motivations for research participation were similar to those described in the literature, including the opportunity to assist in better understanding and ultimately treating AD, gaining access to novel medications, improving outcomes for future generations, and the ability to gain a community of those who understand the impact of the disease (20, 23). Prior studies have shown that patients and families impacted by DIAD are particularly motivated to participate in clinical research due to the high morbidity and mortality of the disease and the large impact the disease has on families, leading to high recruitment and retention rates similar to what were seen within this study (11). Participation in clinical trials provide support and potential treatment in the present and an avenue for hope that the burden of disease will be lessened for those in the future.
Though participants with AD face similar challenges to participating in clinical trials as other disease patient populations, there are also unique barriers in this population that can have significant effects on trial recruitment, retention, and satisfaction. A large amount of time and effort are often required for administering medications, annual visits and other logistical aspects related to participate in research. Study procedures including regular cognitive testing, lumbar punctures, and neuroimaging pose a major mental health burden for participants (23). In addition, trial activities and study visits also require a study partner to support in trial activities. Completing these tasks on top of adjusting to life with a risk for AD or a family member with AD can pose a large mental, physical, and emotional burden (8). This is especially relevant in a population with mean age at onset at 30-50 years, when work, child-raising, and career goals are quite different than when sporadic AD occurs in later decades, typically during retirement.
These barriers to participation require clinical trial researchers to be deliberate in study design to alleviate the burden of participation for participants and their families. Addressing barriers to trial participation is critical to attaining target enrollment numbers with a representative population and low dropout rates, which affect study cost and validity9. Ultimately, there cannot be a significant progression towards a cure or effective treatment for AD without clinical trial participation, making the alleviation of obstacles especially important.
To address some of these unique challenges involved in AD research, this study also offered the possibility of using HHNs to conduct home visits for trial related activities. This service enabled DIAD families that live remotely from a DIAN-TU trial site the opportunity to participate and engage with the trial. Study results demonstrate that the majority of those with the option of utilizing HHN services chose to do so and had generally positive experiences. The availability and convenience of home health nursing services helped to lower the barriers to trial engagement particularly with this population of patients affected by AD who face unique barriers to clinical trial participation, including increased time and effort on the part of both the clinical trial participant and study partners. Literature demonstrates that home visits are one of the most valued trial interventions that can increase likelihood of study participation in patients and families impacted by AD (9). Previous studies have also shown that close facilitation of clinical trial involvement and positive participant-staff relationships can decrease the participant dropout rate due to inconvenience and have overall positive influence on clinical trial participation and satisfaction (19). Overall, our research staff was highly rated by participants and free-text responses reflected positively on the clinical and research team.
The time, effort, and distress related to trial procedures are relevant factors that influence trial satisfaction, engagement, and dropout rates. In this survey, cognitive testing, lumbar punctures, and neuroimaging scans were features of the trial that were noted to cause physical discomfort and emotional distress. Further, the participation in the clinical trial itself was noted by some participants to be a constant reminder of the disease, which may have impacted their overall satisfaction with trial participation. These factors are commonly cited within AD research as barriers to trial participation16. Awareness of these challenges and sufficient education targeted to these areas by trial staff may work to build further trust with participants and alleviate some of the related dissatisfaction.
The present results should be interpreted within the context of the study’s limitations. To help maintain survey anonymity, data on cognitive status and trial completion among responders were not collected, which may create a bias towards positive perceptions if those who completed the trial were the main respondents. The gap between trial end and survey distribution may have contributed to the low response rate. Lastly, due to DIAD’s cognitive decline, some respondents needed assistance to complete the survey, potentially introducing bias between direct and indirect participants’ views. In addition, although we recognized the commitment of DIAD populations to research, and the favorable 3:1 drug to placebo randomization, and relative low dropout rate, we may have received surveys responses from those most invested in the trial, and most likely to endorse a positive experience. Additionally, survey responses were received from participants enrolled in 15 out of 24 DIAN-TU trial sites which may contribute to further bias.
For future trials, it is crucial to incorporate feedback from both family members and trial participants. DIAN studies continue to collate participant input via surveys, webinars, family conferences, and regional family. These sessions, potentially involving brief surveys or interviews, are designed to understand participants’ experiences and their reasons for continuing or discontinuing participation. Such approaches will provide real-time insights, enabling trial adjustments to enhance participant experience and retention. This method is particularly relevant for addressing and understanding the reasons for dropouts, thereby identifying specific challenges for future trial improvements. Adopting this multi-feedback mechanism can offer a more comprehensive and authentic portrayal of experiences, concerns, and insights from those deeply involved in the clinical trial design and protocol. Additionally, in upcoming DIAN studies, we will ensure that Home Health Nurse (HHN) services are an option for every participant, allowing them to decide whether to utilize these services.

 

Conclusions

This analysis delved into participant satisfaction within the context of the DIAN-TU-001 clinical trial. Findings revealed a study population characterized by a marked enthusiasm for research participation, notable contentment with both the trial staff and its logistics, and an expressed readiness for future research involvement. The insights garnered from this exploration are not only vital for the DIAN-TU’s prospective clinical endeavors but also offer valuable lessons for other trials involving participants with AD, shaping the landscape of future research practices.

 

Author contributions: H.L, J.L, E.Z, and J.L and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors were involved in sample and data collection. Study concept and design: H.L, J.L, E.Z and J.L.; Acquisition, analysis, or interpretation of data: H.L, J.L, and J.L. Drafting of the manuscript: H.L. J.L, E.Z, and J.L Critical revision of the manuscript for important intellectual content: All authors. Obtained funding: R.J.B. Project administration: R.J.B. Study supervision: J.L.

Acknowledgements: We gratefully acknowledge the outstanding commitment of the participants, family members, and caregivers whose participation was critical to the success of the DIAN-TU trial. We thank the DIAN-TU study team (https://dian.wustl.edu/our-research/clinical-trial/funding/) for their exceptional dedication and accomplishments, which ensured the success of the trial. We thank the DIAN EXR and DIAN OBS study teams for their support on recruitment and commitment to family members. We appreciate the robust intellectual collaboration between the DIAN-TU investigators, participants and family members, F. Hoffmann-La Roche, Ltd./Genentech, and Eli Lilly and Company, the DIAN-TU Pharma Consortium (https://dian.wustl.edu/our-research/the-pharma-consortium/), the NIH, and regulatory representatives who were critical in making this study possible. We thank the Alzheimer’s Association, GHR Foundation, an anonymous organization, other industry partners (Avid Radiopharmaceuticals, a wholly-owned subsidiary of Eli Lilly and Company, Signant, and Cogstate), and regulatory representatives for their support. We also acknowledge Dr. Laurie Ryan from the National Institute on Aging for her key contributions in leadership and scientific guidance on this project.

Supported by: Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers U01AG042791, U01AG042791-S1 (FNIH and Accelerating Medicines Partnership), R01AG046179, R01AG053267-S1. This research was also supported by the Alzheimer’s Association, Eli Lilly and Company, F. Hoffman-LaRoche Ltd., Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company, GHR Foundation, an anonymous organization. Cogstate, and Signant offered in-kind support. The DIAN-OBS was supported by the National Institute on Aging of the National Institutes on Aging (DIAN, U19AG032438), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI).

Conflict of interest: EMM receives Grant Funding from NIA; Institutional funding from Eli Lilly, Hoffmann-La Roche, Eisai. He is a DSMB member (paid directly) for Alector; Eli Lilly; a Scientific Advisory Board Member (paid directly to me) for Alzamend, Fondation Alzheimer. He acts as a Consultant/Advisor for Sage Therapeutics, Eli Lilly, Sanofi, AstraZeneca,Hoffmann La-Roche. DBC is Medical Director for DIAN-TU and supported by DIAN-TU grants in this role. He receives research support from National Institute of Mental Health, National Institute of Neurological Diseases and Stroke, National Institute of Aging, National Institute of AIDS and Infectious Disease He has served on DSMB or adjudication committees for Sanofi/Genzyme, Wave Life Sciences, Seagen, Atara Biotherapeutics, Teva, CellEvolve, Excision Biotherapeutics and Arena. He receives support for contributing to Up-To-Date. BJS is the site principal investigator for DIAN-TU at Washington University and receives research support from NIH, Eli Lilly, Biogen, Hoffman LaRoche, Eisai and Janssen. She has served on advisory boards for Eisai and Biogen. CJM has received grants from Biogen; honoraria or advisory board fees from Biogen, Eli Lilly, Roche, IONIS, Eisai, Alector; participated in company sponsored symposia for Biogen and Eisai. RJB is the Director of the DIAN-TU and Principal Investigator of the DIAN-TU-001. He receives research support from the National Institute on Aging of the National Institutes of Health, DIAN-TU Trial Pharmaceutical Partners (Eli Lilly and Company, F. Hoffman-La Roche, Ltd., and Avid Radiopharmaceuticals), Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN-TU Pharma Consortium (Active: AbbVie, Biogen, BMS, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche, Ltd./Genentech,. Previous: Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience). CHvD receives research support from the National Institute on Aging of the National Institutes of Health, Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche, Ltd./Genentech, UCB, and Cerevel. He serves as a consultant for F. Hoffman La Roche, Ltd., Eisai, Ono, and Cerevel. SG is member of scientific advisory boards of Alzheon, AmyriAD, Eisai, Enigma USA, Lilly, Medesis, NovoNordisk, Okutsa. Editorial board member JPAD, Neurotorium. DG is paid consultant for Esai and Roche Diagnostics. GYRH discloses that he has received grants or contracts from CIHR, NIA/NIH, has been a clinical trials investigator supported by Anavex, Biogen, Cassava, and Lilly, and has participated in expert advisory committee supported by Biogen, Eisai, Roche, and NovoNordisk. Dr. Hsiung is the current president of C5R (Consortium of Canadian Centres for Clinical Cognitive Research). JP is member of an IDMC for Biogen. EDR serves on a data monitoring committee for Eli Lilly, has received licensing fees from Genentech, and has served as a consultant for AGTC. All other authors have nothing to disclose.

Ethical standards: The protocol was approved by ethics committees at participating sites, and all participants provided written informed consent. The survey was conducted under the DIAN-TU trial central Institutional Review Board (IRB) for US sites, and local IRBs in Australia, Canada, France, Spain, and the UK. No additional consent was required to complete the survey.

 

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