The proof is in the pudding: Patient Engagement in Studying Cannabidiol in Mild Cognitive Impairment

The proof is in the pudding: Patient Engagement in Studying Cannabidiol in Mild Cognitive Impairment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The proof is in the pudding: Patient Engagement in Studying Cannabidiol in Mild Cognitive Impairment Antonia Keck, Julia-Sophia Scheuermann, Petra Scheerbaum, Elmar Graessel, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4984666/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Patient engagement (PE) in clinical trials has gained importance yet remains uncommon, particularly in patients with mild cognitive impairment (MCI), a critical precursor to Alzheimer's disease (AD). Cannabidiol (CBD) shows potential in slowing MCI progression due to its neuroprotective properties. In CBD research, PE is underutilized too. To design a study on CBD for MCI, we administered an online survey to individuals with MCI to better understand their preferences for trial setup and outcomes. Methods We asked 209 individuals with MCI to complete an online survey assessing (i) willingness to participate in a trial using CBD; (ii) importance of improvements in various domains; (iii) acceptance of adverse events (AEs); (iv) reasons for AE-related dropout; (v) willingness to undergo blood sampling and lumbar puncture to assess AD pathology; and (vi) willingness to participate in a trial with a 50% chance of receiving a placebo. Data were analyzed with descriptive statistics. Results N = 118 agreed to participate and N = 88 completed the survey. Participants prioritized improvement in cognitive abilities (87.5%), followed by quality of life (63.6%), daily activities (55.7%), sleep (55.7%), pain (52.3%), mood (52.3%), behavior (48.9%), and anxiety (43.2%). Headache (55.7%) was the least accepted AE followed by nausea (46.6%), fatigue (35.2%), and diarrhea (35.2%). Persistent diarrhea (90.9%) and severe fatigue (84.1%) were the main reasons for potential dropout. While most would undergo blood sampling (67.0%), only a minority (21.6%) would accept lumbar puncture. One-third were ready to participate (34.1%), while 54.5% were interested pending details. Among those in favor of participation, 71.6% would participate even with a 50% chance of placebo. Conclusions Our study identified cognitive improvement as highly relevant for patients, indicating cognitive assessment tools as primary endpoints in MCI research. Given concerns about AEs, dose titration should be carefully considered to enhance acceptance and prevent AEs. Blood sampling seems well-accepted for AD biomarker assessment. Despite potential AEs, participation in a trial using CBD for MCI is seen as attractive, even under placebo-controlled conditions. This cross-sectional study emphasizes the importance of patient engagement in designing high-quality trials for using CBD to treat MCI. Mild cognitive impairment Alzheimer’s disease cannabidiol cannabis-based medicine patient engagement patient and public involvement Figures Figure 1 Figure 2 Figure 3 Background Active patient engagement (PE) in which patients function as genuine partners in clinical trials – particularly in drug development – has gained enormous importance in recent years. Today, PE is regarded as the gold standard in all steps of study design due to the growing awareness of the gap between patient needs and research practices 1 . It is generally accepted that joint action between patient partners and academic researchers is crucial for increasing the focus on patient-centered healthcare 1 . Zvonareva et al. 2 proposed a framework for conceptualizing the intensity of PE in drug research comprising four levels: consultation, involvement, collaboration, and patient-controlled. However, PE is not yet common in drug research trials. Although a range of disease areas are addressed in trials comprising PE activities, many disease areas still lack PE activities in drug research 2 . By actively engaging patient partners in determining how to conduct trials, it will be more likely not only that unmet clinical needs will be answered but also that participant recruitment and adherence will be facilitated. To the best of our knowledge, PE has not yet been applied when designing a randomized controlled trial (RCT) to investigate the effectiveness and safety of a compound in people with mild cognitive impairment (MCI). MCI can be considered a precursor to dementia – as the transition rate is approximately 70% within 5 years 3 – and is often based on Alzheimer’s pathology 4 . In many cases, direct PE is no longer possible after the disease progresses and transitions into Alzheimer's disease (AD) because medical decisions have to be made by patients’ legal representatives on behalf of the individual in the AD stage of the disease 5 , but people with MCI are fully legally competent. MCI is defined as an impairment of cognitive abilities that occurs in older age and that is significantly below the typical performance for the respective age and education level. However, MCI does not come with significant limitations in activities of daily living and, thus, it is significantly different from dementia. Since AD represents a significant challenge for both individuals and society 6 , an evidence-based pharmacological treatment for MCI is urgently needed but is currently unavailable 7 . The fact that MCI is easy to diagnose offers the unique chance to implement a treatment that will reduce the chance that it will transition into AD. The cannabinoid known as cannabidiol (CBD) has been identified as a promising candidate for slowing down the progression of MCI and therefore delaying the transition to AD due to its neuroprotective and anti-inflammatory properties 8 . In addition, CBD is safe and generally well-tolerated, also because of its lack of untoward psychoactive sequelae. So far, only a few studies have actively incorporated PE when studying the effectiveness and safety of cannabis-based medicines in different indications 9 . Remarkably, approval of highly purified CBD (Epidiolex®) to treat seizures in two rare forms of epilepsy (Lennox-Gastaut syndrome and Dravet syndrome) in 2018 was significantly initiated by the fact that the mother of Charlotte, a little girl with Dravet syndrome, had self-initiated adjunctive therapy with a high concentration of CBD from the tetrahydrocannabinol (THC) strain of cannabis to reduce the frequency of Charlotte's seizures 10 . This story impressively shows the benefits of engaging patients and their relatives or caregivers in initiating new pharmacological therapy strategies. As part of our planned RCT investigating the effectiveness and safety of CBD in people with MCI, we aimed to directly involve patient partners in all steps of the study. To be able to implement this plan, we administered an online survey to people diagnosed with MCI who had participated in a recent trial at our center 11 . With this approach, we aimed to design an RCT that uses the outcomes that are most relevant for participants, that is more convenient for participants with respect to adverse events (AEs), and that takes practical aspects into account, such as acceptance of additional investigations. Here, we present the results of the first online survey administered to people with MCI to ask about matters of convenience and their preferences regarding the setup of a clinical trial. Methods Study Design and Participants We contacted N = 209 people who had previously been diagnosed with MCI at our center and who had recently participated in a non-pharmacological trial (for further information, see Scheerbaum et al. 11 ) via email in December 2023. Of these, N = 118 agreed to participate and – after giving written informed consent – were sent a link to the online survey (SoSci Survey; version 3.5.01) 12 . Out of these N = 118 people, N = 103 opened the survey, and N = 88 completed it. To reduce participants’ burden and the time they needed to invest in the study and because collecting participants’ characteristics was not the main focus of this study, we did not collect data on patients’ characteristics in the current study, since these data were available in the study we had recently conducted 11 . However, since the data were collected anonymously, it was not possible to identify the N = 88 individuals who participated in this study out of the sample of N = 118 who had agreed to participate. In order to provide sample characteristics at least by approximation, we present the participant characteristics of the N = 118 individuals who had initially agreed to participate and who were sent the survey link. This information refers to the baseline data in Scheerbaum et al. 11 . Table 1 presents the sample characteristics. Table 1 Characteristics of people with MCI who agreed to participate (N = 118) as approximation for actual participants (N = 88) Variable N Descriptive data Age: years, M a ( SD b ) 118 70.5 (6.6) Sex: female, n (%) 118 63 (53.4) MoCA c sum score, M ( SD ) 118 22.4 (1.6) B-ADL d sum score, M ( SD ) 115 i 1.6 (0.6) Education level (ISCED e ) low n (%) 118 4 (3.4) medium n (%) 118 41 (34.7) high n (%) 118 73 (61.9) Household income per month: Euro, n ( % ) 118 500 - < 1,000 3 (2.5) 1,000 - < 1,500 6 (5.1) 1,500 - < 2,000 13 (11.0) 2,000 - < 2,500 19 (16.1) 2,500 - < 3,500 23 (19.5) 3,000 and more 50 (42.4) not specified 4 (3.4) Employed: yes, n (%) 118 27 (22.9) Depressiveness: PHQ-9 f score, M ( SD ) 118 3.9 (2.9) Vascular risk: sum score g , M ( SD ) 116 i 1.1 (0.9) smoking: yes, n (%) 118 4 (3.4) hypertension: yes, n (%) 118 51 (43.2) hypercholesterolaemia: yes, n (%) 118 59 (50.0) diabetes: yes, n (%) 116 i 16 (13.6) BMI h : M ( SD ) 118 25.6 (4.6) Note. a M = Mean; b SD = Standard Deviation; c MoCA = Montreal Cognitive Assessment; d B-ADL = Bayer Activities of Daily Living Scale; e ISCED = International Standard Classification of Education; f PHQ-9 = Patient Health Questionnaire 9; g Number of vascular risk factors: range 0 (no vascular risk factor) to 4 (four vascular risk factors); h BMI = Body Mass Index, normal Range: 18.5–24.9; i There were missing data on B-ADL (3 cases), vascular risk sum score, and diabetes (2 cases each) considered to be missing completely at random (MCAR). Online Survey Participants were informed about the purpose of the survey. In detail, they received the information that the planned trial "BrainFit-CBD" was designed to investigate the effectiveness and safety of CBD in people with MCI. Furthermore, participants were explicitly informed that the purpose of the survey was to learn more about the needs, wishes, concerns, and suggestions of people with MCI in order to be able to take these results into account while designing the study further. In total, the survey comprised 14 questions. It took participants an average of 7.72 minutes ( SD = 2.98) to complete the survey. Before the survey was launched, we asked two people with MCI to evaluate the survey's clarity, comprehensibility, and completeness via an online video interview conducted by one of the authors (AK). The survey contained the following topics: (i) importance of improvements (1 = not important to 5 = very important) in various domains including cognitive abilities, activities of daily living, mood, anxiety, behavior, pain, sleep, and quality of life, (ii) acceptance of AEs from CBD (1 = fully acceptable to 5 = not at all acceptable) including the most common AEs from CBD (diarrhea, nausea, fatigue, and headache); (iii) reasons for dropout due to AEs, including persistent diarrhea, mild fatigue, severe fatigue, and mild headache (yes/no); (iv) willingness to undergo blood sampling and lumbar puncture to assess AD pathology (yes; basically yes, but more information is needed; no), and (v) general willingness to participate in a trial investigating the effectiveness and safety of CBD in MCI (yes; basically yes, but more information is needed; no), and more specifically, willingness to participate in an RCT with a 50% chance of receiving a placebo (yes/no). Statistics Data were analyzed with descriptive statistics (frequencies, ranges, percentage, means, and standard deviations), calculated with SPSS version 28. Provision of supplementary information for participants To align with the concept of patient engagement, we empowered participants by providing them with supplementary information on CBD in lay language and expressed our appreciation for their participation by sending a thank you email following the administration of the survey. Ethical Considerations The procedures for our recent trial 11 , which included sending voluntary follow-up surveys to the study participants, were approved by the Ethics Committee of the Medical Faculty from the Friedrich-Alexander-Universität Erlangen-Nürnberg (Ref. 21-318-1-B). Results Patients’ characteristics The sample of N = 118 (mean age = 70.6 ( ± 6.6) years, N = 63 (53.4%) women) – who had agreed to participate – had a mean Montreal Cognitive Assessment score of 22.4 ( SD = 1.6), indicating MCI 13 . The majority of these people (61.9%, n = 73) had a high level of education, according to the International Standard Classification of Education 14 . Almost one quarter (22.9%, n = 27) were employed. The mean Patient Health Questionnaire-9 15 score was 3.9 ( SD = 2.9), indicating the absence of depression. On average, people had normal body weight with a Body Mass Index of 25.6 ( SD = 4.6) and had a low level of vascular risk ( M = 1.1, SD = 0.9) calculated as the sum of present vascular risk factors, namely, smoking, hypertension, hypercholesterolaemia, and diabetes. For additional details, see Table 1 . Online Survey The following results refer to data provided by the N = 88 participants who completed the survey. For all the clinical outcomes we assessed, the majority of participants indicated that each outcome was “very important” to them. However, improvement in cognitive abilities was rated as the most important treatment goal (by 87.5% of participants, n = 77) followed by (in descending order) quality of life (63.6%, n = 56), activities of daily living (55.7%, n = 49), sleep (55.7%, n = 49), pain (52.3%, n = 46), mood (52.3%, n = 46), behavior (48.9%, n = 43), and anxiety (43.2%, n = 38). Figure 1 presents the detailed importance ratings of the patient-relevant outcomes. As the least acceptable AE, 55.7% ( n = 49) of all participants rated headache as “not at all acceptable,” followed by nausea (46.6%, n = 41), fatigue (35.2%, n = 31), and diarrhea (35.2%, n = 31). Figure 2 presents the acceptance of AEs as evaluated by participants. Persistent diarrhea was rated as the AE that would most frequently lead to study dropout (indicated by 90.9%, n = 80), followed by severe fatigue (84.1%, n = 74), mild headache (37.5%, n = 33), and mild fatigue (15.9%, n = 14). Figure 3 presents probable study dropout due to non-tolerance of AEs as evaluated by participants. With respect to additional study investigations, 67.0% of participants ( n = 59) stated that they would be willing to undergo blood sampling to assess AD pathology, while only 21.6% ( n = 19) agreed to accept a lumbar puncture for this purpose. Additionally, 31.8% ( n = 28) and 37.5% ( n = 33) of participants, respectively, indicated that they might be willing to accept these additional investigations but would need more information. Most of the respondents were in favor of participating in a trial for testing CBD for MCI, as 34.1% ( n = 30) indicated their willingness to participate and another 54.5% ( n = 47) stated that they might be willing to participate but would need more information. Of those who chose one of the two “yes” answers (“yes” and “basically yes, but more information is needed”), 71.6% ( n = 63) stated that they would also participate in the RCT even if the chance of receiving a placebo was 50%. Discussion This survey aimed to incorporate PE when setting up an RCT to investigate the effectiveness and safety of CBD in treating MCI. In our sample, people with MCI considered improvement in cognitive abilities to be the most important clinical outcome. This finding is consistent with the ICD-11 diagnostic criteria, which identify cognitive impairment as the central symptom of MCI 16 . To conduct patient-relevant research, our findings support the use of a cognitive assessment tool as the primary endpoint, while also considering additional patient-relevant outcomes – such as quality of life, sleep, and activities of daily living – as key secondary endpoints. In clinical routine settings, the diagnosis of MCI is made on the basis of the results of clinical assessments such as the Montreal Cognitive Assessment 13 or Mini-Mental-State-Examination 17 . According to German guidelines for the diagnosis of AD 7 , it is strongly recommended that either a lumbar puncture for cerebrospinal fluid (CSF) analyses or positron emission tomography (PET) imaging are additionally performed to collect and examine AD biomarkers, including amyloid plaques, neurofibrillary tangles, and neurodegeneration. However, PET imaging is extremely expensive, has only limited availability, is time consuming, and is therefore hardly possible in the context of larger RCTs, while lumbar puncture is invasive and may cause side effects. We were therefore interested in whether people with MCI would be willing to accept a lumbar puncture as an additional investigation in an RCT using CBD. Non-surprisingly, only one fifth of participants indicated their willingness to undergo CSF analyses and another third of patients asked for further information (although written patient information on lumbar puncture was already included in the survey). By contrast, blood sampling was much more accepted by this group of participants, suggesting that, as an alternative to CSF analyses, plasma levels of AD biomarkers should be used to confirm a diagnosis of MCI, although, until now, promising plasma biomarkers for AD (e.g., phosphorylated tau 217; p-tau217) have still been slightly less sensitive than CSF analyses and PET imaging. Additional advantages of blood sample analyses are generally lower costs and general accessibility 18 . With respect to AEs, people with MCI have indicated persistent diarrhea and severe fatigue as AEs that have led to study drop out. This information is important, as the most common side effects of high dose treatments of CBD are diarrhea, nausea, fatigue, and headache, among others 19 – 21 . So far, no RCTs have been available to investigate the efficacy and safety of CBD in people with MCI. Accordingly, the optimal dose of CBD is also unknown. Based on effects of CBD in other psychiatric indications, it can be assumed that higher doses may be more effective 22 . However, the results of this survey clearly indicate that, in an RCT, the dose titration of CBD should consider the importance of AEs, such as diarrhea and severe fatigue. Interestingly, in general, participating in an RCT to test the use of CBD seems to be highly attractive to people with MCI. In addition, our results emphasize the need for involvement and informed decision-making, as more than half of the participants requested additional information before participating in the study. As most of the individuals expressed their willingness to participate even if given a placebo, a placebo-controlled trial for CBD appears to be feasible. Although our study provided valuable insights into PE for planning a trial to test the use of CBD to treat MCI, it is important to acknowledge the limitations of our study. First, due to the inability to match responses with participants, our sample description included individuals who did not participate in the survey, thus rendering it an inaccurate representation of those who indeed completed it. Second, the survey assessments were hypothetical, making different decisions (e.g., regarding treatment discontinuation due to certain side effects) in an actual study possible. Third, our sample consisted of individuals who had already participated in a non-pharmacological trial for MCI, and so they were familiar with the study procedures. Thus, the sample may have been biased because of their general willingness to participate in a clinical trial, and such willingness may have influenced their responses to some extent. Conclusions In summary, this study is the first to incorporate PE into a trial on the use of CBD for MCI, as there are currently no existing PE activities in this area. It provides valuable insights into the concerns, aims, and needs of people with MCI and offers initial implications for planning and conducting future studies involving this population. Our main message is to encourage the incorporation of PE activities in the drug research process, not only to reflect the goals and needs of patients but also to improve the quality of research. Abbreviations AD Alzheimer’s Disease AE(s) Adverse event(s) CBD Cannabidiol CSF Cerebrospinal Fluid M Arithmetic Mean MCI Mild Cognitive Impairment PE Patient Engagement PET Positron Emission Tomography RCT Randomized Controlled Trial THC Tetrahydrocannabinol Declarations Ethics approval and consent to participate The procedures were approved by the Ethics Committee of the Medical Faculty of the Friedrich-Alexander-Universität Erlangen-Nürnberg (Ref. 21-318-1-B). Informed consent was obtained from all individuals included in the study. Participants were provided with comprehensive information about the study's purpose, and procedures before receiving the link to the online survey. Participation was entirely voluntary, and participants had the option to withdraw from the survey at any point before submission. Consent for publication All participants provided consent for their anonymized data to be used in the publication. No identifying information is included in the manuscript, and every effort has been made to ensure the privacy and confidentiality of participant data. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Conflict of Interest The authors declare no conflicts of interest. Funding This work is supported by the Karl and Veronica Carstens-Stiftung http://dx.doi.org/10.13039/501100006709; KVC 0/117/2021E Disclaimer The funding body played no role in the study design, the collection, analysis, or interpretation of the data, or in writing the manuscript. Authors’ contributions Antonia Keck (AK) drafted the manuscript and constructed the tables and figures. AK, Kirsten R. Mueller-Vahl (KMV), and Elmar Graessel (EG) were responsible for the conception of the survey and considered the survey questions. Julia-Sophia Scheuermann (JS) and Petra Scheerbaum (PS) structured the recruitment process and collected the patients’ characteristics. AK set up the online survey and performed the data analyses. JS, PS, EG, and KMV made substantial contributions to the manuscript and critically revised it. All authors have read and approved the final version of the manuscript. EG and KMV share last authorship. The present work was performed in partial fulfillment of the requirements for obtaining the degree “Dr. rer. biol. hum.” by Antonia Keck. Acknowledgments We would like to express our gratitude to all those who participated in the survey and provided data, as well as to those who pre-evaluated the survey for offering valuable insights that contributed to the conceptualization of a patient-centered survey. We would also like to thank Martin Schmitt for his support in implementing the online survey. We also thank our English language editor, Dr. Jane Zagorski. Clinical trial number Clinical trial number: not applicable. References Faulkner SD, Somers F, Boudes M, Nafria B, Robinson P. Using Patient Perspectives to Inform Better Clinical Trial Design and Conduct: Current Trends and Future Directions. Pharmaceut Med. 2023;37(2):129–38. Zvonareva O, Craveț C, Richards DP. Practices of patient engagement in drug development: a systematic scoping review. Res Involv Engagem. 2022;8(1):29. 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Update on Cannabidiol Clinical Toxicity and Adverse Effects: A Systematic Review. Curr Neuropharmacol. 2023;21(11):2323–42. Chesney E, Oliver D, Green A, Sovi S, Wilson J, Englund A, et al. Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology. 2020;45(11):1799–806. Dammann I, Rohleder C, Leweke FM. Cannabidiol and its Potential Evidence-Based Psychiatric Benefits –. Crit Rev Pharmacopsychiatry. 2024;57(03):115–32. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 06 Sep, 2024 Editor assigned by journal 06 Sep, 2024 Submission checks completed at journal 05 Sep, 2024 First submitted to journal 27 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4984666","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":350480296,"identity":"555f335c-d3f7-4c39-bf6c-60fecb016eef","order_by":0,"name":"Antonia Keck","email":"data:image/png;base64,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","orcid":"","institution":"Universitätsklinikum Erlangen","correspondingAuthor":true,"prefix":"","firstName":"Antonia","middleName":"","lastName":"Keck","suffix":""},{"id":350480297,"identity":"f3b65122-8dae-4e60-8cfb-06ff29dcba2d","order_by":1,"name":"Julia-Sophia Scheuermann","email":"","orcid":"","institution":"Universitätsklinikum Erlangen","correspondingAuthor":false,"prefix":"","firstName":"Julia-Sophia","middleName":"","lastName":"Scheuermann","suffix":""},{"id":350480298,"identity":"b998ef9b-d074-49ae-9481-635be0648497","order_by":2,"name":"Petra Scheerbaum","email":"","orcid":"","institution":"Universitätsklinikum Erlangen","correspondingAuthor":false,"prefix":"","firstName":"Petra","middleName":"","lastName":"Scheerbaum","suffix":""},{"id":350480299,"identity":"7be41ffe-4c96-412b-8470-fa90e6ffa2fa","order_by":3,"name":"Elmar Graessel","email":"","orcid":"","institution":"Universitätsklinikum Erlangen","correspondingAuthor":false,"prefix":"","firstName":"Elmar","middleName":"","lastName":"Graessel","suffix":""},{"id":350480300,"identity":"4e1a873e-279e-4d4c-8990-174eb6bf5b05","order_by":4,"name":"Kirsten R. Mueller-Vahl","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Kirsten","middleName":"R.","lastName":"Mueller-Vahl","suffix":""}],"badges":[],"createdAt":"2024-08-27 12:52:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4984666/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4984666/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67101987,"identity":"ae9bc629-20c6-44ad-a681-4f161089d116","added_by":"auto","created_at":"2024-10-21 08:19:04","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":209863,"visible":true,"origin":"","legend":"\u003cp\u003eRelevance of clinical outcomes as evaluated by participants (N = 88). Note, ADL = Activities of daily living; MBI = Mild behavioral impairment; QoL = Quality of life.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4984666/v1/a397009a75c088140c6e5272.jpg"},{"id":67101989,"identity":"6d5aec94-5bd3-4962-b08c-8d9cc133fc9f","added_by":"auto","created_at":"2024-10-21 08:19:04","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":145688,"visible":true,"origin":"","legend":"\u003cp\u003eNon-acceptance of adverse events of cannabidiol as evaluated by participants (N = 88).\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4984666/v1/39038263f9f320eed681554a.jpg"},{"id":67101990,"identity":"4ad31fe5-8703-4922-a3d0-8e25f1bdd682","added_by":"auto","created_at":"2024-10-21 08:19:04","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":157382,"visible":true,"origin":"","legend":"\u003cp\u003eFrequency of probable discontinuation of the study depending on side effects of cannabidiol as evaluated by participants (N = 88).\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4984666/v1/07ceac430b823ef1a36003a2.jpg"},{"id":67103274,"identity":"ea1f52de-6af7-4ff6-87dc-a2e636a24859","added_by":"auto","created_at":"2024-10-21 08:27:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1018435,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4984666/v1/391e86d1-f51e-481a-9c16-1ec7ead6bb92.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The proof is in the pudding: Patient Engagement in Studying Cannabidiol in Mild Cognitive Impairment","fulltext":[{"header":"Background","content":"\u003cp\u003eActive patient engagement (PE) in which patients function as genuine partners in clinical trials \u0026ndash; particularly in drug development \u0026ndash; has gained enormous importance in recent years. Today, PE is regarded as the gold standard in all steps of study design due to the growing awareness of the gap between patient needs and research practices \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. It is generally accepted that joint action between patient partners and academic researchers is crucial for increasing the focus on patient-centered healthcare\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Zvonareva et al.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e proposed a framework for conceptualizing the intensity of PE in drug research comprising four levels: consultation, involvement, collaboration, and patient-controlled. However, PE is not yet common in drug research trials. Although a range of disease areas are addressed in trials comprising PE activities, many disease areas still lack PE activities in drug research\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. By actively engaging patient partners in determining how to conduct trials, it will be more likely not only that unmet clinical needs will be answered but also that participant recruitment and adherence will be facilitated.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, PE has not yet been applied when designing a randomized controlled trial (RCT) to investigate the effectiveness and safety of a compound in people with mild cognitive impairment (MCI). MCI can be considered a precursor to dementia \u0026ndash; as the transition rate is approximately 70% within 5 years\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e \u0026ndash; and is often based on Alzheimer\u0026rsquo;s pathology\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In many cases, direct PE is no longer possible after the disease progresses and transitions into Alzheimer's disease (AD) because medical decisions have to be made by patients\u0026rsquo; legal representatives on behalf of the individual in the AD stage of the disease\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, but people with MCI are fully legally competent. MCI is defined as an impairment of cognitive abilities that occurs in older age and that is significantly below the typical performance for the respective age and education level. However, MCI does not come with significant limitations in activities of daily living and, thus, it is significantly different from dementia. Since AD represents a significant challenge for both individuals and society\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, an evidence-based pharmacological treatment for MCI is urgently needed but is currently unavailable\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The fact that MCI is easy to diagnose offers the unique chance to implement a treatment that will reduce the chance that it will transition into AD.\u003c/p\u003e \u003cp\u003eThe cannabinoid known as cannabidiol (CBD) has been identified as a promising candidate for slowing down the progression of MCI and therefore delaying the transition to AD due to its neuroprotective and anti-inflammatory properties\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. In addition, CBD is safe and generally well-tolerated, also because of its lack of untoward psychoactive sequelae. So far, only a few studies have actively incorporated PE when studying the effectiveness and safety of cannabis-based medicines in different indications\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Remarkably, approval of highly purified CBD (Epidiolex\u0026reg;) to treat seizures in two rare forms of epilepsy (Lennox-Gastaut syndrome and Dravet syndrome) in 2018 was significantly initiated by the fact that the mother of Charlotte, a little girl with Dravet syndrome, had self-initiated adjunctive therapy with a high concentration of CBD from the tetrahydrocannabinol (THC) strain of cannabis to reduce the frequency of Charlotte's seizures\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. This story impressively shows the benefits of engaging patients and their relatives or caregivers in initiating new pharmacological therapy strategies.\u003c/p\u003e \u003cp\u003eAs part of our planned RCT investigating the effectiveness and safety of CBD in people with MCI, we aimed to directly involve patient partners in all steps of the study. To be able to implement this plan, we administered an online survey to people diagnosed with MCI who had participated in a recent trial at our center\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. With this approach, we aimed to design an RCT that uses the outcomes that are most relevant for participants, that is more convenient for participants with respect to adverse events (AEs), and that takes practical aspects into account, such as acceptance of additional investigations.\u003c/p\u003e \u003cp\u003eHere, we present the results of the first online survey administered to people with MCI to ask about matters of convenience and their preferences regarding the setup of a clinical trial.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003eWe contacted \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;209 people who had previously been diagnosed with MCI at our center and who had recently participated in a non-pharmacological trial (for further information, see Scheerbaum et al. \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e) via email in December 2023. Of these, \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;118 agreed to participate and \u0026ndash; after giving written informed consent \u0026ndash; were sent a link to the online survey (SoSci Survey; version 3.5.01)\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Out of these \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;118 people, \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;103 opened the survey, and \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;88 completed it. To reduce participants\u0026rsquo; burden and the time they needed to invest in the study and because collecting participants\u0026rsquo; characteristics was not the main focus of this study, we did not collect data on patients\u0026rsquo; characteristics in the current study, since these data were available in the study we had recently conducted \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. However, since the data were collected anonymously, it was not possible to identify the \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;88 individuals who participated in this study out of the sample of \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;118 who had agreed to participate. In order to provide sample characteristics at least by approximation, we present the participant characteristics of the \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;118 individuals who had initially agreed to participate and who were sent the survey link. This information refers to the baseline data in Scheerbaum et al.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the sample characteristics.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eCharacteristics of people with MCI who agreed to participate (N\u0026thinsp;=\u0026thinsp;118) as approximation for actual participants (N\u0026thinsp;=\u0026thinsp;88)\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDescriptive data\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eAge: years, \u003cem\u003eM\u003c/em\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e (\u003cem\u003eSD\u003c/em\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70.5 (6.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eSex: female, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63 (53.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eMoCA\u003csup\u003ec\u003c/sup\u003e sum score, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eSD\u003c/em\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.4 (1.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eB-ADL\u003csup\u003ed\u003c/sup\u003e sum score, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eSD\u003c/em\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e115\u003csup\u003ei\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.6 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation level (ISCED\u003csup\u003ee\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elow \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emedium \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41 (34.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehigh \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73 (61.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHousehold income per month: Euro, \u003cem\u003en\u003c/em\u003e (\u003cem\u003e%\u003c/em\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e500 - \u0026lt; 1,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (2.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1,000 - \u0026lt; 1,500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1,500 - \u0026lt; 2,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (11.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2,000 - \u0026lt; 2,500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19 (16.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2,500 - \u0026lt; 3,500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 (19.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3,000 and more\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50 (42.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enot specified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eEmployed: yes, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27 (22.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDepressiveness: PHQ-9\u003csup\u003ef\u003c/sup\u003e score, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eSD\u003c/em\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.9 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVascular risk:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003esum score\u003csup\u003eg\u003c/sup\u003e, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eSD\u003c/em\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e116\u003csup\u003ei\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.1 (0.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003esmoking: yes, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ehypertension: yes, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51 (43.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ehypercholesterolaemia: yes, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ediabetes: yes, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e116\u003csup\u003ei\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (13.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eBMI\u003csup\u003eh\u003c/sup\u003e: \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eSD\u003c/em\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.6 (4.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eNote.\u003c/em\u003e \u003csup\u003ea\u003c/sup\u003e\u003cem\u003eM\u003c/em\u003e = Mean; \u003csup\u003eb\u003c/sup\u003e\u003cem\u003eSD\u003c/em\u003e = Standard Deviation; \u003csup\u003ec\u003c/sup\u003eMoCA = Montreal Cognitive Assessment; \u003csup\u003ed\u003c/sup\u003eB-ADL\u0026thinsp;=\u0026thinsp;Bayer Activities of Daily Living Scale; \u003csup\u003ee\u003c/sup\u003eISCED = International Standard Classification of Education; \u003csup\u003ef\u003c/sup\u003ePHQ-9\u0026thinsp;=\u0026thinsp;Patient Health Questionnaire 9; \u003csup\u003eg\u003c/sup\u003eNumber of vascular risk factors: range 0 (no vascular risk factor) to 4 (four vascular risk factors); \u003csup\u003eh\u003c/sup\u003eBMI = Body Mass Index, normal Range: 18.5\u0026ndash;24.9; \u003csup\u003ei\u003c/sup\u003eThere were missing data on B-ADL (3 cases), vascular risk sum score, and diabetes (2 cases each) considered to be missing completely at random (MCAR).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u0026lt;Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026gt;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOnline Survey\u003c/h2\u003e \u003cp\u003eParticipants were informed about the purpose of the survey. In detail, they received the information that the planned trial \"BrainFit-CBD\" was designed to investigate the effectiveness and safety of CBD in people with MCI. Furthermore, participants were explicitly informed that the purpose of the survey was to learn more about the needs, wishes, concerns, and suggestions of people with MCI in order to be able to take these results into account while designing the study further. In total, the survey comprised 14 questions. It took participants an average of 7.72 minutes (\u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.98) to complete the survey. Before the survey was launched, we asked two people with MCI to evaluate the survey's clarity, comprehensibility, and completeness via an online video interview conducted by one of the authors (AK).\u003c/p\u003e \u003cp\u003eThe survey contained the following topics: (i) importance of improvements (1\u0026thinsp;=\u0026thinsp;not important to 5\u0026thinsp;=\u0026thinsp;very important) in various domains including cognitive abilities, activities of daily living, mood, anxiety, behavior, pain, sleep, and quality of life, (ii) acceptance of AEs from CBD (1\u0026thinsp;=\u0026thinsp;fully acceptable to 5\u0026thinsp;=\u0026thinsp;not at all acceptable) including the most common AEs from CBD (diarrhea, nausea, fatigue, and headache); (iii) reasons for dropout due to AEs, including persistent diarrhea, mild fatigue, severe fatigue, and mild headache (yes/no); (iv) willingness to undergo blood sampling and lumbar puncture to assess AD pathology (yes; basically yes, but more information is needed; no), and (v) general willingness to participate in a trial investigating the effectiveness and safety of CBD in MCI (yes; basically yes, but more information is needed; no), and more specifically, willingness to participate in an RCT with a 50% chance of receiving a placebo (yes/no).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eData were analyzed with descriptive statistics (frequencies, ranges, percentage, means, and standard deviations), calculated with SPSS version 28.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eProvision of supplementary information for participants\u003c/h2\u003e \u003cp\u003e To align with the concept of patient engagement, we empowered participants by providing them with supplementary information on CBD in lay language and expressed our appreciation for their participation by sending a thank you email following the administration of the survey.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eEthical Considerations\u003c/h2\u003e \u003cp\u003eThe procedures for our recent trial \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, which included sending voluntary follow-up surveys to the study participants, were approved by the Ethics Committee of the Medical Faculty from the Friedrich-Alexander-Universit\u0026auml;t Erlangen-N\u0026uuml;rnberg (Ref. 21-318-1-B).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; characteristics\u003c/h2\u003e \u003cp\u003eThe sample of \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;118 (mean age\u0026thinsp;=\u0026thinsp;70.6 (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;6.6) years, \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;63 (53.4%) women) \u0026ndash; who had agreed to participate \u0026ndash; had a mean Montreal Cognitive Assessment score of 22.4 (\u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.6), indicating MCI\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. The majority of these people (61.9%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;73) had a high level of education, according to the International Standard Classification of Education\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Almost one quarter (22.9%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27) were employed. The mean Patient Health Questionnaire-9\u003csup\u003e15\u003c/sup\u003e score was 3.9 (\u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.9), indicating the absence of depression. On average, people had normal body weight with a Body Mass Index of 25.6 (\u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.6) and had a low level of vascular risk (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.1, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9) calculated as the sum of present vascular risk factors, namely, smoking, hypertension, hypercholesterolaemia, and diabetes. For additional details, see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eOnline Survey\u003c/h2\u003e \u003cp\u003eThe following results refer to data provided by the \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;88 participants who completed the survey. For all the clinical outcomes we assessed, the majority of participants indicated that each outcome was \u0026ldquo;very important\u0026rdquo; to them. However, improvement in cognitive abilities was rated as the most important treatment goal (by 87.5% of participants, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;77) followed by (in descending order) quality of life (63.6%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;56), activities of daily living (55.7%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;49), sleep (55.7%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;49), pain (52.3%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;46), mood (52.3%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;46), behavior (48.9%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;43), and anxiety (43.2%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;38). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the detailed importance ratings of the patient-relevant outcomes.\u003c/p\u003e \u003cp\u003eAs the least acceptable AE, 55.7% (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;49) of all participants rated headache as \u0026ldquo;not at all acceptable,\u0026rdquo; followed by nausea (46.6%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;41), fatigue (35.2%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;31), and diarrhea (35.2%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;31). Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the acceptance of AEs as evaluated by participants.\u003c/p\u003e \u003cp\u003ePersistent diarrhea was rated as the AE that would most frequently lead to study dropout (indicated by 90.9%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;80), followed by severe fatigue (84.1%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;74), mild headache (37.5%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;33), and mild fatigue (15.9%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14). Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents probable study dropout due to non-tolerance of AEs as evaluated by participants.\u003c/p\u003e \u003cp\u003eWith respect to additional study investigations, 67.0% of participants (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;59) stated that they would be willing to undergo blood sampling to assess AD pathology, while only 21.6% (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;19) agreed to accept a lumbar puncture for this purpose. Additionally, 31.8% (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;28) and 37.5% (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;33) of participants, respectively, indicated that they might be willing to accept these additional investigations but would need more information.\u003c/p\u003e \u003cp\u003eMost of the respondents were in favor of participating in a trial for testing CBD for MCI, as 34.1% (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;30) indicated their willingness to participate and another 54.5% (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;47) stated that they might be willing to participate but would need more information. Of those who chose one of the two \u0026ldquo;yes\u0026rdquo; answers (\u0026ldquo;yes\u0026rdquo; and \u0026ldquo;basically yes, but more information is needed\u0026rdquo;), 71.6% (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;63) stated that they would also participate in the RCT even if the chance of receiving a placebo was 50%.\u003c/p\u003e \u003cp\u003e\u0026lt;Figure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026gt;\u003c/p\u003e \u003cp\u003e\u0026lt;Figure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026gt;\u003c/p\u003e \u003cp\u003e\u0026lt;Figure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026gt;\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis survey aimed to incorporate PE when setting up an RCT to investigate the effectiveness and safety of CBD in treating MCI. In our sample, people with MCI considered improvement in cognitive abilities to be the most important clinical outcome. This finding is consistent with the ICD-11 diagnostic criteria, which identify cognitive impairment as the central symptom of MCI\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. To conduct patient-relevant research, our findings support the use of a cognitive assessment tool as the primary endpoint, while also considering additional patient-relevant outcomes \u0026ndash; such as quality of life, sleep, and activities of daily living \u0026ndash; as key secondary endpoints.\u003c/p\u003e \u003cp\u003eIn clinical routine settings, the diagnosis of MCI is made on the basis of the results of clinical assessments such as the Montreal Cognitive Assessment\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e or Mini-Mental-State-Examination\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. According to German guidelines for the diagnosis of AD\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, it is strongly recommended that either a lumbar puncture for cerebrospinal fluid (CSF) analyses or positron emission tomography (PET) imaging are additionally performed to collect and examine AD biomarkers, including amyloid plaques, neurofibrillary tangles, and neurodegeneration. However, PET imaging is extremely expensive, has only limited availability, is time consuming, and is therefore hardly possible in the context of larger RCTs, while lumbar puncture is invasive and may cause side effects. We were therefore interested in whether people with MCI would be willing to accept a lumbar puncture as an additional investigation in an RCT using CBD. Non-surprisingly, only one fifth of participants indicated their willingness to undergo CSF analyses and another third of patients asked for further information (although written patient information on lumbar puncture was already included in the survey). By contrast, blood sampling was much more accepted by this group of participants, suggesting that, as an alternative to CSF analyses, plasma levels of AD biomarkers should be used to confirm a diagnosis of MCI, although, until now, promising plasma biomarkers for AD (e.g., phosphorylated tau 217; p-tau217) have still been slightly less sensitive than CSF analyses and PET imaging. Additional advantages of blood sample analyses are generally lower costs and general accessibility\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWith respect to AEs, people with MCI have indicated persistent diarrhea and severe fatigue as AEs that have led to study drop out. This information is important, as the most common side effects of high dose treatments of CBD are diarrhea, nausea, fatigue, and headache, among others\u003csup\u003e\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. So far, no RCTs have been available to investigate the efficacy and safety of CBD in people with MCI. Accordingly, the optimal dose of CBD is also unknown. Based on effects of CBD in other psychiatric indications, it can be assumed that higher doses may be more effective\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. However, the results of this survey clearly indicate that, in an RCT, the dose titration of CBD should consider the importance of AEs, such as diarrhea and severe fatigue.\u003c/p\u003e \u003cp\u003eInterestingly, in general, participating in an RCT to test the use of CBD seems to be highly attractive to people with MCI. In addition, our results emphasize the need for involvement and informed decision-making, as more than half of the participants requested additional information before participating in the study. As most of the individuals expressed their willingness to participate even if given a placebo, a placebo-controlled trial for CBD appears to be feasible.\u003c/p\u003e \u003cp\u003eAlthough our study provided valuable insights into PE for planning a trial to test the use of CBD to treat MCI, it is important to acknowledge the limitations of our study. First, due to the inability to match responses with participants, our sample description included individuals who did not participate in the survey, thus rendering it an inaccurate representation of those who indeed completed it. Second, the survey assessments were hypothetical, making different decisions (e.g., regarding treatment discontinuation due to certain side effects) in an actual study possible. Third, our sample consisted of individuals who had already participated in a non-pharmacological trial for MCI, and so they were familiar with the study procedures. Thus, the sample may have been biased because of their general willingness to participate in a clinical trial, and such willingness may have influenced their responses to some extent.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, this study is the first to incorporate PE into a trial on the use of CBD for MCI, as there are currently no existing PE activities in this area. It provides valuable insights into the concerns, aims, and needs of people with MCI and offers initial implications for planning and conducting future studies involving this population. Our main message is to encourage the incorporation of PE activities in the drug research process, not only to reflect the goals and needs of patients but also to improve the quality of research.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAlzheimer\u0026rsquo;s Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAE(s)\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse event(s)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCBD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCannabidiol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebrospinal Fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eArithmetic Mean\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMild Cognitive Impairment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePatient Engagement\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePositron Emission Tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRandomized Controlled Trial\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTHC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTetrahydrocannabinol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch3\u003eEthics approval and consent to participate\u003c/h3\u003e\n\u003cp\u003eThe procedures were approved by the Ethics Committee of the Medical Faculty of the Friedrich-Alexander-Universit\u0026auml;t Erlangen-N\u0026uuml;rnberg (Ref. 21-318-1-B). Informed consent was obtained from all individuals included in the study. Participants were provided with comprehensive information about the study\u0026apos;s purpose, and procedures before receiving the link to the online survey. Participation was entirely voluntary, and participants had the option to withdraw from the survey at any point before submission.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eConsent for publication\u003c/h3\u003e\n\u003cp\u003eAll participants provided consent for their anonymized data to be used in the publication. No identifying information is included in the manuscript, and every effort has been made to ensure the privacy and confidentiality of participant data.\u003c/p\u003e\n\u003ch3\u003eAvailability of data and materials\u003c/h3\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch3\u003eConflict of Interest\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eThis work is supported by the Karl and Veronica Carstens-Stiftung http://dx.doi.org/10.13039/501100006709; KVC 0/117/2021E\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eDisclaimer\u003c/h3\u003e\n\u003cp\u003eThe funding body played no role in the study design, the collection, analysis, or interpretation of the data, or in writing the manuscript.\u003c/p\u003e\n\u003ch3\u003eAuthors\u0026rsquo; contributions\u003c/h3\u003e\n\u003cp\u003eAntonia Keck (AK) drafted the manuscript and constructed the tables and figures. AK, Kirsten R. Mueller-Vahl (KMV), and Elmar Graessel (EG) were responsible for the conception of the survey and considered the survey questions. Julia-Sophia Scheuermann (JS) and Petra Scheerbaum (PS) structured the recruitment process and collected the patients\u0026rsquo; characteristics. AK set up the online survey and performed the data analyses. JS, PS, EG, and KMV made substantial contributions to the manuscript and critically revised it. All authors have read and approved the final version of the manuscript. EG and KMV share last authorship. The present work was performed in partial fulfillment of the requirements for obtaining the degree \u0026ldquo;Dr. rer. biol. hum.\u0026rdquo; by Antonia Keck.\u003c/p\u003e\n\u003ch3\u003eAcknowledgments\u003c/h3\u003e\n\u003cp\u003eWe would like to express our gratitude to all those who participated in the survey and provided data, as well as to those who pre-evaluated the survey for offering valuable insights that contributed to the conceptualization of a patient-centered survey. We would also like to thank Martin Schmitt for his support in implementing the online survey. We also thank our English language editor, Dr. Jane Zagorski.\u003c/p\u003e\n\u003ch3\u003eClinical trial number\u003c/h3\u003e\n\u003cp\u003eClinical trial number: not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFaulkner SD, Somers F, Boudes M, Nafria B, Robinson P. Using Patient Perspectives to Inform Better Clinical Trial Design and Conduct: Current Trends and Future Directions. Pharmaceut Med. 2023;37(2):129\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZvonareva O, Craveț C, Richards DP. Practices of patient engagement in drug development: a systematic scoping review. Res Involv Engagem. 2022;8(1):29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInui Y, Ito K, Kato T. Longer-Term Investigation of the Value of 18F-FDG-PET and Magnetic Resonance Imaging for Predicting the Conversion of Mild Cognitive Impairment to Alzheimer\u0026rsquo;s Disease: A Multicenter Study. J Alzheimer\u0026rsquo;s Disease. 2017;60(3):877\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTahami Monfared AA, Byrnes MJ, White LA, Zhang Q. Alzheimer\u0026rsquo;s Disease: Epidemiology and Clinical Progression. Neurol Ther. 2022;11(2):553\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirschman KB, Xie SX, Feudtner C, Karlawish JHT. How Does an Alzheimer\u0026rsquo;s Disease Patient\u0026rsquo;s Role in Medical Decision Making Change Over Time? J Geriatr Psychiatry Neurol. 2004;17(2):55\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTahami Monfared AA, Byrnes MJ, White LA, Zhang Q. The Humanistic and Economic Burden of Alzheimer\u0026rsquo;s Disease. Neurol Ther. 2022;11(2):525\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDGN DGPPN. S3-Leitlinie Demenzen. 2016.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbate G, Uberti D, Tambaro S. Potential and Limits of Cannabinoids in Alzheimer\u0026rsquo;s Disease Therapy. Biology (Basel). 2021;10(6):542.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eModaresi F, Talachian K. The Characteristics of Clinical Trials on Cannabis and Cannabinoids: A Review of Trials for Therapeutic or Drug Development Purposes. Pharmaceut Med. 2022;36(6):387\u0026ndash;400.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55(6):783\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScheerbaum P, Book S, Jank M, Hanslian E, DellO\u0026rsquo;ro M, Schneider J et al. Computerised cognitive training tools and online nutritional group counselling for people with mild cognitive impairment: study protocol of a completely digital, randomised, controlled trial. BMJ Open. 2022;12(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeiner DJ. SoSci Survey (Version 3.5.02) [Computer software]. 2024. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.soscisurvey.de\u003c/span\u003e\u003cspan address=\"https://www.soscisurvey.de\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNasreddine ZS, Phillips NA, B\u0026eacute;dirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For Mild Cognitive Impairment. J Am Geriatr Soc. 2005;53(4):695\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUNESCO Institute for Statistics. International Standard Classification of Education (ISCED) 2011. Montr\u0026eacute;al. 2012.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKroenke K, Spitzer RL, Williams JBW. The PHQ-9 -Validity of a Brief Depression Severity Measure. J Gen Intern Med. 2001;16(9):606\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. International statistical classification of diseases and related health problems (11th ed.). 2021. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://icd.who.int/\u003c/span\u003e\u003cspan address=\"https://icd.who.int/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFolstein MF, Folstein SE, McHugh PR. Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGonzalez-Ortiz F, Kac PR, Brum WS, Zetterberg H, Blennow K, Karikari TK. Plasma phospho-tau in Alzheimer\u0026rsquo;s disease: towards diagnostic and therapeutic trial applications. Mol Neurodegener. 2023;18(1):18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSouza JDR, Pacheco JC, Rossi GN, de-Paulo BO, Zuardi AW, Guimar\u0026atilde;es FS, et al. Adverse Effects of Oral Cannabidiol: An Updated Systematic Review of Randomized Controlled Trials (2020\u0026ndash;2022). Pharmaceutics. 2022;14(12):2598.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMadeo G, Kapoor A, Giorgetti R, Busard\u0026ograve; FP, Carlier J. Update on Cannabidiol Clinical Toxicity and Adverse Effects: A Systematic Review. Curr Neuropharmacol. 2023;21(11):2323\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChesney E, Oliver D, Green A, Sovi S, Wilson J, Englund A, et al. Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology. 2020;45(11):1799\u0026ndash;806.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDammann I, Rohleder C, Leweke FM. Cannabidiol and its Potential Evidence-Based Psychiatric Benefits \u0026ndash;. Crit Rev Pharmacopsychiatry. 2024;57(03):115\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-complementary-medicine-and-therapies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcam","sideBox":"Learn more about [BMC Complementary Medicine and Therapies](https://bmccomplementmedtherapies.biomedcentral.com/)","snPcode":"","submissionUrl":"","title":"BMC Complementary Medicine and Therapies","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Mild cognitive impairment, Alzheimer’s disease, cannabidiol, cannabis-based medicine, patient engagement, patient and public involvement","lastPublishedDoi":"10.21203/rs.3.rs-4984666/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4984666/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePatient engagement (PE) in clinical trials has gained importance yet remains uncommon, particularly in patients with mild cognitive impairment (MCI), a critical precursor to Alzheimer's disease (AD). Cannabidiol (CBD) shows potential in slowing MCI progression due to its neuroprotective properties. In CBD research, PE is underutilized too. To design a study on CBD for MCI, we administered an online survey to individuals with MCI to better understand their preferences for trial setup and outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe asked 209 individuals with MCI to complete an online survey assessing (i) willingness to participate in a trial using CBD; (ii) importance of improvements in various domains; (iii) acceptance of adverse events (AEs); (iv) reasons for AE-related dropout; (v) willingness to undergo blood sampling and lumbar puncture to assess AD pathology; and (vi) willingness to participate in a trial with a 50% chance of receiving a placebo. Data were analyzed with descriptive statistics.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;118 agreed to participate and \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;88 completed the survey. Participants prioritized improvement in cognitive abilities (87.5%), followed by quality of life (63.6%), daily activities (55.7%), sleep (55.7%), pain (52.3%), mood (52.3%), behavior (48.9%), and anxiety (43.2%). Headache (55.7%) was the least accepted AE followed by nausea (46.6%), fatigue (35.2%), and diarrhea (35.2%). Persistent diarrhea (90.9%) and severe fatigue (84.1%) were the main reasons for potential dropout. While most would undergo blood sampling (67.0%), only a minority (21.6%) would accept lumbar puncture. One-third were ready to participate (34.1%), while 54.5% were interested pending details. Among those in favor of participation, 71.6% would participate even with a 50% chance of placebo.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur study identified cognitive improvement as highly relevant for patients, indicating cognitive assessment tools as primary endpoints in MCI research. Given concerns about AEs, dose titration should be carefully considered to enhance acceptance and prevent AEs. Blood sampling seems well-accepted for AD biomarker assessment. Despite potential AEs, participation in a trial using CBD for MCI is seen as attractive, even under placebo-controlled conditions. This cross-sectional study emphasizes the importance of patient engagement in designing high-quality trials for using CBD to treat MCI.\u003c/p\u003e","manuscriptTitle":"The proof is in the pudding: Patient Engagement in Studying Cannabidiol in Mild Cognitive Impairment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-21 08:18:59","doi":"10.21203/rs.3.rs-4984666/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-06T10:43:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-06T08:20:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-05T07:55:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Complementary Medicine and Therapies","date":"2024-08-27T12:51:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-complementary-medicine-and-therapies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcam","sideBox":"Learn more about [BMC Complementary Medicine and Therapies](https://bmccomplementmedtherapies.biomedcentral.com/)","snPcode":"","submissionUrl":"","title":"BMC Complementary Medicine and Therapies","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"35a23e4e-f4c3-4ab7-a032-0196fbaecdc0","owner":[],"postedDate":"October 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-01-08T09:08:05+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-21 08:18:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4984666","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4984666","identity":"rs-4984666","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}