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Declarations | PMC9969622 | |||
Ethics approval and consent to participate {24} | The trial is currently ongoing. The protocol was approved by the ethical committee board (CCER 2019–02469) in April 2020 and by ClinicalTrials.gov (Identifier: NCT04479397) in July 2020. All patients agree to participate, and a written consent will be obtained from all participants. | PMC9969622 | ||
Availability of data and materials {29} | All data will be available on request at the following email address: alexandre.laedermann@gmail.com. | PMC9969622 | ||
Consent for publication {32} | Informed consent from was approved by the ethical committee board (CCER 2019–02469) in April 2020. No identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. Informed consent materials are available from the corresponding author on request. | PMC9969622 | ||
Competing interests {28} | FOUNDER | AL is a paid consultant for Stryker, Medacta, and Arthrex. He receives royalties from Stryker. He is the founder of FORE, BeeMed, and Med4Cast. He owns stock options of Medacta, BeeMed, and FollowHealth. The other authors declare that they have no competing interests. | PMC9969622 | |
References | PMC9969622 | |||
Subject terms | Treatment failure occurs in about 25% of patients with methicillin-susceptible New treatments are essential for methicillin-susceptible | PMC10579052 | ||
Results | MSSA bacteremia | MAY | Between 31 May 2019 and 24 February 2022, we assessed 925 patients with MSSA bacteremia for eligibility. After excluding 710 patients who were considered ineligible, we enrolled 215 patients, who were randomly assigned to receive cloxacillin plus fosfomycin ( | PMC10579052 |
Trial profile. | MSSA | CONSORT diagram indicating participant numbers and disposition throughout the course of the trail. *51 patients had more than one exclusion criterion.The primary endpoint was treatment success at day 7 after randomization, a composite endpoint comprising the following criteria: patient alive, stable or with improved quick sequential organ failure assessment (qSOFA) score, afebrile and with negative blood cultures for MSSA. In a planned interim analysis performed when half of the sample size had been recruited, an independent committee blinded to treatment allocation recommended stopping randomization because its members estimated that it was highly unlikely that statistically significant superiority of the combination therapy would be achieved with full enrollment (data regarding this decision are provided in the | PMC10579052 | |
Primary and secondary endpoints | SECONDARY | The results for primary and secondary endpoints in the intention-to-treat population are shown in Fig. | PMC10579052 | |
Discussion | comorbidity, endocarditis, bacteremia, infection, MSSA bacteremia, bloodstream infections | BLOODSTREAM INFECTION, RECURRENCE, ENDOCARDITIS, ADVERSE EVENTS, DISEASE, RECRUITMENT, INFECTION, SECONDARY | This open-label, phase III–IV superiority randomized clinical trial conducted in 19 Spanish hospitals aimed to evaluate whether the combination of cloxacillin and fosfomycin achieved better treatment success than cloxacillin alone in patients with MSSA bacteremia. The primary endpoint was chosen based on the recommendations of international experts that proposed primary endpoints for use in clinical trials comparing treatment options for bloodstream infections in adultsThe main finding of our trial is that cloxacillin plus fosfomycin did not achieve better treatment success at day 7 than cloxacillin alone among patients with MSSA bacteremia. Secondary endpoints, including adverse events leading to discontinuation of therapy, were similar in the two treatment groups, with the exception of persistent bacteremia at day 3, which was less common in the combination treatment arm.The results of our study are in line with the findings of the few randomized clinical trials carried out to date assessing different antibiotic combinations, which have also failed to improve treatment success rates and outcomes in patients with MSSA bacteremia and endocarditis, as shown in a recent meta-analysisAs stated above, we found that persistent bacteremia at day 3 after randomization was less frequent in patients receiving cloxacillin plus fosfomycin than in patients receiving cloxacillin alone. However, this finding did not translate into improved survival at day 7. This result contrasts with those of some observational studies that have found that each day of persistent bacteremia is associated with increased mortalityWe did not find significant differences in all-cause mortality at day 7 or at end of therapy and TOC visits. Nevertheless, mortality at TOC was higher in patients treated with cloxacillin alone, although the difference was not statistically significant. Of note, median age, the proportion of male patients, mean Charlson comorbidity index score and the prevalence of implants were slightly higher in patients receiving cloxacillin alone, who were also more likely to have a high-risk source of bacteremia, including endocarditis at TOC. Moreover, mortality was low in both treatment groups, and the trial was not powered to detect survival differences.We found similar rates of adverse events leading to treatment discontinuation during the first 7 days of therapy in the two study groups. In a previous trial comparing daptomycin plus fosfomycin versus daptomycin alone in patients with methicillin-resistant Our study has limitations. The first is the open-label design, which may have introduced a bias in the assessment of treatment success. Nevertheless, this limitation was mitigated by including objective data in the composite primary endpoint, which was also adjudicated by an independent committee blinded to treatment allocation. It should be noted that our trial mainly focused on treatment effect during the first 7 days (when fosfomycin was administered in the combination treatment arm) and assessed relevant secondary endpoints at TOC (12 weeks after randomization). Therefore, we cannot rule out disease recurrence or relapse occurring beyond 12 weeks after randomization. Unfortunately, there are no standardized primary endpoints to be used in trials comparing different strategies for antibiotic treatment of MSSA bacteremia, and efforts should be made to reach consensus regarding the endpoints that should be used in future trials. Another limitation of our study is that it was conducted in a single country, and its findings might not be generalizable to other populations. Furthermore, when enrollment of half of the sample size had been achieved, the independent committee raised no concerns regarding safety, but mentioned the differences between the success rate specified in the sample size calculation and the rate observed in the planned interim analysis, and recommended ceasing patient recruitment owing to futility. Moreover, the number of patients who had high-risk MSSA bacteremia was relatively low, and the trial was not powered to detect survival differences. Finally, our trial did not include patients with prosthetic endocarditis, therefore we cannot draw conclusions about the hypothetical benefits of adjunctive fosfomycin in this setting.In conclusion, cloxacillin plus fosfomycin did not achieve better treatment success at day 7 of therapy than cloxacillin alone in hospitalized adult patients with MSSA bacteremia. Further large randomized controlled trials should be conducted to evaluate new strategies of treatment aimed at improving outcomes in patients with MSSA bacteremia. Ideally, these trials should be designed taking into account the intrinsic heterogeneity of the infection, by using a more stratified and personalized approach and by including a long-term follow-up. | PMC10579052 |
Methods | PMC10579052 | |||
Study design and setting | MSSA bacteremia | MAY | We performed an open-label, phase III–IV superiority randomized clinical trial of patients with MSSA bacteremia at 19 Spanish university hospitals (the SAFO trial). Participants were recruited from May 2019 to February 2022. Before inclusion in the trial, all patients or legal representatives provided written informed consent. All participants were able to withdraw from the study at any time without further explanation. The study was authorized by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS; 18-0905) and by the Bellvitge University Hospital Ethics Committee (AC069/18). The protocol has been published elsewhere | PMC10579052 |
Participants | death, allergy, MSSA, liver cirrhosis, non-type, active infection | CHRONIC HEART FAILURE, HYPERSENSITIVITY REACTION, PROSTHETIC VALVE ENDOCARDITIS, ALLERGY, LIVER CIRRHOSIS, HEART | Adult patients aged ≥18 years with at least one blood culture positive for MSSA ≤ 72 h before randomization, with evidence of active infection, were considered eligible for inclusion in the study. Treatment with any anti-staphylococcal antibiotic ≤72 h preceding randomization was allowed. Exclusion criteria were severe clinical status with expected death in <24 h; severe liver cirrhosis (Child–Pugh C); moderate-to-severe chronic heart failure (New York Heart Association functional classification, class III–IV); suspicion of prosthetic valve endocarditis; history of significant allergy to beta-lactam antibiotics or fosfomycin (defined as previous type 1 hypersensitivity reaction to any beta-lactam antibiotics or fosfomycin, or history of serious non-type 1 hypersensitivity reaction to any penicillin or fosfomycin); known non-susceptibility of | PMC10579052 |
Randomization and masking | Participants were randomly assigned (1:1) to receive cloxacillin plus fosfomycin or cloxacillin alone, for the initial 7 days of treatment. A centralized electronic computer randomization schedule was developed by the Biostatistics Unit at the Bellvitge Biomedical Research Institute (IDIBELL). The randomization was performed in computer-generated variable blocks ranging from four to six patients stratified per center to conceal the sequence until the intervention was assigned. The code numbers for eligible participants were assigned in ascending sequential order. The allocation list was stored at IDIBELL and was not available to any member of the research team. At each participating hospital, patients who provided written informed consent and met the study criteria were randomized by investigators, who obtained the assigned treatment and code number from a computer-assisted website. | PMC10579052 | ||
Outcomes | bacteremia, infection, MSSA | ENDOCARDITIS, ADVERSE EVENTS, INFECTION, SECONDARY, STERILE | The primary study endpoint was treatment success at day 7, a composite endpoint defined as the presence of all of the following criteria: patient alive, stable or with improved qSOFA score compared with baseline, afebrile and with negative blood cultures for MSSA. The primary endpoint was adjudicated by an independent committee blinded to the antibiotic therapy received by participants. Withdrawal of study medication for any reason before day 7 was considered treatment failure. A hierarchical analysis of treatment success had been planned at TOC only if there had been statistical differences in the primary endpoint at day 7. The analysis at day 7 would provide an early indication of whether the antibiotic was effective in controlling the infection.The secondary clinical endpoints were all-cause mortality at day 7, end of therapy and TOC visits, persistent bacteremia (at least one positive blood culture) at day 3 and day 7 after randomization, microbiological treatment failure (defined as a positive sterile site culture for MSSA at least 14 days after randomization), relapsing bacteremia (defined as at least one positive blood culture for MSSA at least 72 h after a preceding negative culture) assessed at TOC, complicated bacteremia (defined as persistent bacteremia, endocarditis, metastatic emboli or the presence of prosthetic devices), emergence of fosfomycin-resistant strains, length of intensive care unit stay, duration of intravenous antibiotic treatment, and serious adverse events leading to discontinuation of therapy during the first 7 days after randomization.A systematic, prioritized, risk-based approach to the monitoring of adverse events was applied to ensure that the trial was conducted, recorded and reported in accordance with good clinical practicesAll data were recorded on a secure web application for building and managing online databases (REDCap) | PMC10579052 |
Statistical analysis | EVENTS, SECONDARY | On the basis of our own experienceData for the primary and secondary endpoints were analyzed with the intention-to-treat approach and per protocol. The intention-to-treat analysis included all randomly assigned patients who received at least one day of treatment. As the two analyses produced virtually the same results, only the intention-to-treat analysis is presented in detail. All patients who received at least one dose of treatment were included in the safety analysis. Main efficacy analyses and the proportion of treatment success at day 7 were compared between groups using a two-sided chi-squared test. Relative risks for study outcomes were calculated and reported with 95% confidence intervals. The incidences of events in secondary outcomes were compared using the chi-squared test, Fisher’s exact test or the Mann–Whitney test. Kaplan–Meier curves for survival were constructed and compared using the log-rank test. All analyses and data management were performed with R software, v.4.0.4 or later | PMC10579052 | |
Reporting summary | Further information on research design is available in the | PMC10579052 | ||
Online content | Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02569-0. | PMC10579052 | ||
Supplementary information |
Reporting Summary | PMC10579052 | ||
Extended data | is available for this paper at 10.1038/s41591-023-02569-0. | PMC10579052 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02569-0. | PMC10579052 | ||
Acknowledgements | This study was funded by the Spanish Ministry of Health (grant no. PI17/01116), Instituto de Salud Carlos III, Madrid, Spain, and Laboratorios ERN, Barcelona, Spain (grant no. 19PNJ145). We thank the Spanish Clinical Research Network (SCReN), Instituto de Salud Carlos II, for its support through projects PT17/0017/0010 and PT20/000008, integrated into the ‘Plan Estatal de I + D + I’ 2013–2016 and co-financed by the European Regional Development Fund (FEDER). J.M.M. received a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, for the 2017–2024 period. O.G. received a research grant from the ‘Pla estratègic de recerca i innovació en salut (PERIS) 2019–2021’ (Departament de Salut, Generalitat de Catalunya). We also thank the CERCA Program and the Generalitat de Catalunya for institutional support. The funders did not contribute to the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication. | PMC10579052 | ||
Author contributions | M.P. and J.C. were lead investigators. M.P., J.M.M. and J.C contributed to study design and development of concept. S.G., M.P. and J.C drafted the manuscript. N.P. and C.T performed statistical analysis. M.P. obtained funding. S.V., P.H., G.H., D.M., M.S., S.G., M.P., J.C., N.P. and C.T. had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The SAFO study group contributed to data acquisition and critical revision of the manuscript. All authors contributed to acquisition, analysis or interpretation of data, and performed critical revision of the manuscript for important intellectual content. | PMC10579052 | ||
Peer review | PMC10579052 | |||
Data availability | SECONDARY | Individual patient data cannot be shared because of privacy restrictions. Raw anonymized data relating to primary and secondary outcomes and safety can be shared upon request. Depending on the data requested, we will need to consult with the institutional review board at Hospital Universitari de Bellvitge. Requests for data can be sent to the corresponding authors (M.P. and J.C.). All requests will be answered within 4 weeks. | PMC10579052 | |
Competing interests | M.P. received a research grant from Laboratorios ERN. J.M.M. has received consulting honoraria and/or research grants from Angelini Pharma, ContraFect, Genentech, Gilead Sciences, Janssen, Lysovant, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Pfizer and ViiV Healthcare, outside the submitted work. J.L.C. has received speaker honoraria from Pfizer, MSD, AstraZeneca, Guerbet and Hartmann. L.E.L.C. has served as scientific advisor for Angelini Pharma, speaker for Angelini Pharma, ViiV Healthcare, Gilead Sciences and Correvio, and trainer for ViiV Healthcare. J.M.A. has received honoraria for speaking at symposia organised on behalf of Pfizer, Astellas, MSD, Angelini Pharma, Shionogi, Takeda and Gilead Sciences, and has sat on advisory boards on behalf of Pfizer, Astellas, MSD, Angelini Pharma, Gilead Sciences and Takeda. Á.I.C. has received speaker honoraria from Pfizer, Bristol Myers Squibb, Esteve and Bayer. C.T. has received speaker honoraria from Gedeon Richter. G.C. has received support for attending national and international scientific congresses from Angelini Pharma Spain, Pfizer Spain and MSD, and speaker honoraria from Pfizer Spain and Gilead Sciences Europe. J.C. has received speaker honoraria from MSD and Gilead Sciences, and has participated as an investigator in trials on COVID-19 by Roche and Gilead Sciences. The rest of the authors do not declare any conflicts of interest. | PMC10579052 | ||
References | PMC10579052 | |||
Supplementary Information | hand movements | Pre-operative simulated practice allows trainees to learn robotic surgery outside the operating room without risking patient safety. While simulation practice has shown efficacy, simulators are expensive and frequently inaccessible. Cruff (J Surg Educ 78(2): 379–381, 2021) described a low-cost simulation model to learn hand movements for robotic surgery. Our study evaluates whether practice with low-cost home simulation models can improve trainee performance on robotic surgery simulators. Home simulation kits were adapted from those described by Cruff (J Surg Educ 78(2): 379–381, 2021). Hand controllers were modified to mimic the master tool manipulators (MTMs) on the da Vinci Skills Simulator (dVSS). Medical students completed two da Vinci exercises: Sea Spikes 1 (SS1) and Big Dipper Needle Driving (BDND). They were subsequently assigned to either receive a home simulation kit or not. Students returned two weeks later and repeated SS1 and BDND. Overall score, economy of motion, time to completion, and penalty subtotal were collected, and analyses of covariance were performed. Semi-structured interviews assessed student perceptions of the robotic simulation experience. Thirty-three medical students entered the study. Twenty-nine completed both sessions. The difference in score improvement between the experimental and control groups was not significant. In interviews, students provided suggestions to increase fidelity and usefulness of low-cost robotic home simulation. Low-cost home simulation models did not improve student performance on dVSS after two weeks of at-home practice. Interview data highlighted areas to focus future simulation efforts. Ongoing work is necessary to develop low-cost solutions to facilitate practice for robotic surgery and foster more inclusive and accessible surgical education.The online version contains supplementary material available at 10.1007/s11701-023-01688-7. | PMC10492874 | |
Keywords | PMC10492874 | |||
Introduction | Robotic surgery is a positive, enduring innovation that surgeons are increasingly integrating into surgical practice for complex minimally invasive procedures [Various robotic surgery simulators currently are available, including the da Vinci Skills Simulator (dVSS; Intuitive Surgical Inc., Sunnydale, California, USA) with the SimNow learning program, the dV-Trainer (dVT; Mimic Technologies, Inc., Seattle, Washington, USA), RobotiX Mentor (RM; 3D Systems, Littleton, Colorado, USA), SimSurgery Educational Platform Robot (SEP; SimSurgery, Oslo, Norway), and Robotic Surgical Simulator (RoSS; Simulated Surgical Systems LLC, San Jose, California, USA) [A previous study has shown that dVSS outperforms the other two most commonly used VR simulators (dVT and RM) for content validity [While simulation training sessions that provide hands-on practice for robotic surgery are effective, simulators are expensive and not readily accessible to many community surgeons and students [One prior report from Cruff [ | PMC10492874 | ||
Materials and methods | PMC10492874 | |||
Development of home simulation kits | foam suture | PAD | The controllers in the home simulation kits were designed to mimic the MTMs on the dVSS and were modeled from those described by Cruff [Home simulation kits including the hand controllers, peg transfer board, and spongeThe peg transfer board allowed trainees to practice an exercise that mimicked the Sea Spikes 1 task on the SimNow program. The Sea Spikes 1 task requires the trainee to virtually grasp a series of rings and place them on the color concordant cone [The home simulation kits also included a sponge and suturing needles. These materials allowed the participants to practice needle driving with the hand controllers in a manner intended to mimic the Big Dipper Needle Driving task on SimNow. The Big Dipper Needle Driving task is a virtual suturing exercise on a foam suture pad, in which the trainee must drive the needle through a sequence of holes [ | PMC10492874 |
Study design and participants | Volunteer medical students who were novices to robotic surgery were recruited to participate in this study. The University of California, San Francisco (UCSF) Institutional Review Board determined this study to be exempt (IRB22-36266). All participants completed a pre-study survey on general demographics and factors that may affect their performance on the robotic simulator exercises, including video game experience [After completion of this baseline SimNow session, participants were randomly assigned to either receive a robotic home simulation kit with instructions for practice or to receive no home simulation kit. Participants in the experimental group received their home simulation kit immediately following the baseline SimNow session and were instructed to practice with the hand controllers using the peg transfer board and suture supplies for 15 min each day for 2 weeks. Studies have shown that learning a task can be done more effectively when practice sessions are shorter and more frequent [Furthermore, these students received instructional video supplements that outlined proper technique for the peg transfer and needle driving exercises to facilitate correct practice with the home simulation kits. Students in the experimental group were also provided a daily log to detail the specific activities and the time they spent practicing. Two weeks after the baseline SimNow session, all participants returned for another session using the SimNow program on dVSS to repeat the Sea Spikes 1 and Big Dipper Needle Driving tasks (Fig. Flowchart of study design | PMC10492874 | ||
Main study parameters | After each trial of a task, SimNow produces a score report that provides an overall score (out of 100) for the trainee’s performance. In addition to the overall score for each task, the score report is also broken up into various components. The pre-specified performance parameters examined in this study included: (1) time taken to complete the exercise, (2) economy of motion, and (3) penalty sub-score. | PMC10492874 | ||
Statistical analysis | Descriptive statistics regarding the demographics of the participants, including their year in medical school, gender, age, video game use, handedness, and experience in the OR, as well as with laparoscopic surgery and robotic surgery, were assessed using R version 4.1.3. The groups were compared on these demographics using Fisher’s exact test and | PMC10492874 | ||
Qualitative interviews | SECONDARY | Following the second SimNow session, all the students from the experimental and control groups participated in semi-structured debriefing interviews with RW regarding their experience using the robotic surgery simulator during the first and second simulator sessions. As a medical student, RW was chosen to conduct the interviews to allow for the most open and frank discussion with interviewees. Participants in the experimental group were asked additional questions to learn about their experience using the home simulation kit (Supplemental File 2). All interviews were recorded with participant consent and responses were transcribed. The primary goal of these interviews was to understand how specific skills, movements, and knowledge gained from the use of the home simulation kit applied to the robotic surgery simulator exercises on SimNow. The secondary goal of the interviews was to identify common challenges that participants faced when practicing with the home simulation kit and to find any improvements that could be made to the design.All the transcripts were reviewed by two readers (RW and RB) independently and codes were identified using an inductive approach. The readers came to a consensus on developing the codebook. All transcripts were then double-coded, and the codes were reconciled. Themes were identified among coded data. In this analysis and to identify themes, RW brought her perspective as a medical student with no robotic surgery experience, and RB brought his perspective as a surgical resident with robotic surgery experience. | PMC10492874 | |
Results | PMC10492874 | |||
Demographics | Overall, 33 participants completed the first dVSS session, of whom 29 participants completed both dVSS sessions (Fig. Participant demographics and baseline characteristics*Not calculated because sample size was too small to meet statistical assumptions | PMC10492874 | ||
Qualitative interviews | All 29 students who returned for the second robotic simulator session completed the post-session interview immediately following the second task. Through the participant interviews, we identified three main themes of student experience: (1) Novices encounter initial challenges with the robotic simulator that improve with exposure, (2) Practice with the home simulation kit impacts the robotic simulator experience, and (3) The fidelity of the home simulation kit could be improved (Table Qualitative results summary1. Lack of Familiarity – Orienting to the robot– Understanding goals andrules2. Lack of technical skills– Body positioning– Instrument control– Needle handling3. Visuospatial challenges– Depth perceptionFamiliarity—“I wasn’t fully cognizant of all the rules and also just conceptually figuring out how to use the clutch, when to use it, and how to orient yourself while you’re using it was a little bit tricky for me.”Technical skills—“The first time it was hard to maintain both of the arms of the robot in a distance so they don’t collide with themselves, that was challenging. I think I did that a couple times and…I was penalized.”Technical skills—“Just getting used to the clutch was really hard.”Technical skills—“I had a really hard time figuring out the orientation for the needle.”Visuospatial skills—“I feel like just getting used to the disconnect between what you’re seeing and then where your hands are, because not seeing your actual hands while you’re doing something.”1. Technical skills– Needle handling– Wristed movements– Ambidexterity2. FamiliarityTechnical skills—“The needle threading for the home kit was pretty good because you get the dexterity of how to go about putting the needle in one hole and getting it out the other one.”Technical skills—“[The kit helped] needle control and kind of determining which ways I needed to twist my wrist and my fingers in order to get [the needle] to drive through, which definitely translated over here [at the robotic simulator].”Technical skills—“Just being a little bit more ambidextrous with how I did the needle driving activity and trying to use the other hand because I’m predominantly right–handed and I think for the first time I was using predominantly my right hand, but I was…more conscious of which hand I was using [during the second session].”Familiarity—“I learned how to go about the needle driving activity most efficiently, how to angle my hands so that I could basically just put the needle through very easily and seamlessly.”1. Model design transferability– No clutch on home model– More resistance thanrobot2. Mechanical challengesModel design—“If you’re actually threading the needle through the real sponge, you’re going to feel resistance, but here [on the robotic simulator], you don’t feel anything.”Mechanical challenges—“The tips of the tweezers didn’t have much grip either, and so you’re… pressing really, really hard to hold the needle in place, because otherwise it was just slipping out of place. So I guess maybe swap to a different type of tweezer that might have more grip.” | PMC10492874 | ||
Novices encounter initial challenges with the robotic simulator that improve with exposure | hand movements | Students experienced challenges upon initial exposure to the robotic simulator in three areas: (1) familiarity, (2) technical skills, and (3) visuospatial skills. These challenges framed subsequent experiences with home simulation.Many participants found it difficult to orient themselves to the robot and the tasks, as well as understanding the rules and goals of each exercise.“I would say at first the most challenging is just being intentional with all of my hand movements. I wasn’t fully cognizant of all the rules and also just conceptually figuring out how to use the clutch, when to use it, and how to orient yourself while you’re using it was a little bit tricky for me.” (Experimental Participant #18)Even after they became familiar with the simulator, the participants noted that they struggled with using the robot to perform the technical skills required to complete the SimNow tasks, including body positioning, instrument control, and needle handling. Concerning body positioning, students reported difficulties determining how they should orient their arms in physical space under the console of the machine to most effectively and comfortably complete each task on the simulator.“The first time it was hard to maintain both of the arms of the robot in a distance so they don't collide with themselves, that was challenging. I think I did that a couple times and…I was penalized.” (Control Participant #1)Regarding instrument control, most students specified they had initial difficulties with effectively using the clutch on the MTMs to complete the tasks.“Just getting used to the clutch was really hard. I usually forgot to engage the clutch and so I would twist myself into like 35 positions, which made it hard.” (Experimental Participant #27)Students also found needle handling difficult in their initial exposure to the robotic simulator.“I had a really hard time figuring out orientation for the needle…so that I could insert it correctly, and that it came out exactly where I wanted it to, because I would put the needle into the sponge and pretty much have no idea how to turn my hand or where it was basically in the surface.” (Control Participant #16)Students initially experienced challenges with their visuospatial skills, such as depth perception. Many students found it hard to perceive the environment through the VR robotic console and felt they did not have a precise idea of the movements they were making.“I feel like just getting used to the disconnect between what you’re seeing and then where your hands are, because not seeing your actual hands while you’re doing something.” (Control Participant #22)Participants in both the experimental and control groups identified that their abilities changed from the first SimNow session to the second SimNow session. During the second session, they were more familiar with the interface and activities, felt more comfortable with basic skills, and had improved understanding of the depth perception and use of visual cues. | PMC10492874 | |
Practice with the home simulation kit impacts the robotic simulator experience | Within the experimental group, participants attributed a variety of experiences during the second SimNow session to their practice with the home kit, including both technical skills and understanding of the robotic console.In terms of technical skills, participants felt that practicing needle manipulation with the controllers provided with the home simulation kits was useful to develop their dexterity and improve their needle handling and wristed movements.“[The home simulation kit was] helpful to do the motion; just have your fingers in the right place and kind of pick things up and put things down. The sponge was helpful in judging the needle orientation, and the hand motions you need to do the scoop.” (Experimental Participant #12)“[The kit helped] needle control and kind of determining which ways I needed to twist my wrist and my fingers in order to get [the needle] to drive through, which definitely translated over here [at the robotic simulator].” (Experimental Participant #17)Others stated that the home simulation kit helped improve their ambidexterity, a helpful skill for many tasks on the robotic surgery simulator.“Just being a little bit more ambidextrous with how I did the needle driving activity and trying to use the other hand because I’m predominantly right-handed and I think for the first time I was using predominantly my right hand, but I was…more conscious of which hand I was using [during the second session].” (Experimental Participant #18)When probing specifically about how the home simulation kit affected the participants’ haptic feedback, or sense of touch, on the robotic simulator, students highlighted the differences between the haptic sensation in the home kit and that of the robotic simulator.“It's definitely a different haptic feeling. I felt like it was harder to drive the needle through the sponge than it is to drive the needle through the fake robotic sponge. But, just having the haptic feedback was helpful and that is something you get with the home kit.” (Experimental Participant #12)Finally, participants also communicated that the home simulation kit improved their sense of familiarity with the tasks and allowed them to strategize to complete the tasks more efficiently.“I learned how to go about the needle driving activity most efficiently, how to angle my hands so that I could basically just put the needle through very easily and seamlessly.” (Experimental Participant #18)“I think that I was a little bit like, I wouldn’t say slower, but more kind of methodical, and that's something that came from the practice.” (Experimental Participant #4) | PMC10492874 | ||
The fidelity of the home simulation kit could be improved | PAD | While participants found the home kits to be helpful in improving their skills and comfort with the robotic simulator, they also had some suggestions for refining the kits for future use. Their suggestions focused on model design transferability to the robotic simulator, as well as on the mechanical challenges they experienced.Regarding model design transferability, despite the usefulness of the sponge to learn to judge needle orientation and to practice the wrist motions to drive the needle, it had a different feeling than the robotic simulator. In general, participants expressed that using a sponge for the needle driving activity in the home kit produced more resistance than the robotic simulator. Students reported that this difference made it challenging to understand exactly how much pressure should be used when driving the needle on the robotic simulator. Some suggested using another material with less resistance to better mimic the virtual foam and its lack of haptic feedback on the robotic simulator.“If you’re actually threading the needle through the real sponge, you’re going to feel resistance, but here [on the robotic simulator], you don’t feel anything.” (Participant #14)Participants also suggested that it would be helpful to include something on the home kit that would closely resemble the clutch of the robotic simulator.“Maybe put some type of pad for the clutch, because this basically felt slightly different…I got used to pressing with my finger curled up and when I was like, ‘Oh wait, where’s the clutch?’ and I had to re-find the clutch.” (Experimental Participant #26)Regarding mechanical challenges, participants noted that certain parts of the home kit were less comfortable to use or needed to be reinforced to prevent any breakage, interfering with their ability to use the practice kits as directed. Particularly, many students mentioned the difficulties they experienced with the stiffer grip of the tweezers used to design the hand controllers in the home simulation kits.“The tips of the tweezers didn’t have much grip either, and so you’re… pressing really, really hard to hold the needle in place, because otherwise it was just slipping out of place. So I guess maybe swap to a different type of tweezer that might have more grip.” (Experimental Participant #17) | PMC10492874 | |
Discussion | Given the need to provide practice opportunities to prepare learners to use new surgical technologies, this study evaluated home practice for robotic surgery. Overall, low-cost robotic surgery home simulation kits did not lead students to better performance on dVSS compared to control students, though interview data highlighted the potential of home simulation and future directions for simulator development. The score increase in both groups between simulation sessions likely reflects task familiarity on dVSS gained during the first session. Challenges with physical fidelity of the home robotic simulation kits, as discussed by many participants in interviews, may have limited additional skill gains in the home practice group. Furthermore, many participants did not meet the practice goal, likely because home practice was unsupervised and unscheduled. Additionally, the duration of practice was self-reported, which may have been inaccurate and did not account for how correctly the participants practiced. Finally, since medical students are not expected to perfect their robotic surgical skills, they may have less motivation to practice compared to, for example, surgical residents who will be expected to master these skills.For future iterations of the home simulation kit, participants noted the importance of addressing the haptics of the model and choosing appropriate practice tasks. While this feedback from medical students will be important in planning future studies, it would also be helpful to include surgical residents with more experience in further trials. Prior experience with the robot may allow trainees to focus home practice on the most useful skills, while also practicing with better technique, leading to greater overall improvement.There remains a need for a low-cost simulation model to facilitate engagement and accessible practice for robotic surgery. Many trainees do not have formal robotic surgery simulation training curricula in place at their institutions [This study begins to address this need by describing important considerations for low-cost robotic simulator development. Improvements to model design transferability, such as fine-tuning the resistance of the controllers or including a clutch, could potentially lead to more efficacious practice and greater improvements in performance. It was apparent that a number of students in the experimental group showed strong motivation to practice their skills with the home simulation kits. Some students spent several hours practicing with the home kits and found them to be an excellent way to engage with robotic surgical skills. Having additional time to practice at home can be an important component of learning when there is limited student exposure to robotic surgery [In conclusion, the home simulation kits will need to be further refined to better represent the robotic surgery controllers and the practice tasks should be modified to optimize user skill acquisition in the future. However, work with home simulation kits represents the beginning of a needed innovation in robotic surgery. The development of creative, low-cost solutions to practice surgical techniques is essential to reach more potential trainees and foster more inclusive and accessible surgical education. | PMC10492874 | ||
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 15 KB) | PMC10492874 | ||
Author contributions | All authors contributed to the study conception and design. The robotic surgery simulator sessions were run by RW, RB, and NR. Material preparation, data collection and analysis were performed by RW, RB, and PO’S. The first draft of the manuscript was written by RW and RB. All authors had substantial contributions to revising the work and all authors read and approved the final manuscript. | PMC10492874 | ||
Funding | Rachel Wile received funding through UCSF’s Summer Explore Program. Riley Brian receives funding through the UCSF-Intuitive Simulation-Based Surgical Education Research Fellowship. Jason Cruff previously received a grant from Intuitive Surgical with plans to perform a similar research project at his home institution but experienced unforeseen problems with study enrollment, and thus the research could not be completed. None of these funds from Intuitive Surgical were used and the grant was returned. Intuitive Surgical was not involved with any part of this project. The remaining authors did not receive support from any organization for the submitted work. | PMC10492874 | ||
Data availability | The data that support the findings of this study are available on request from the corresponding author, RW. | PMC10492874 | ||
Declarations | PMC10492874 | |||
Competing interests | The authors declare no competing interests. | PMC10492874 | ||
Ethical approval | The University of California, San Francisco (UCSF) Institutional Review Board determined this study to be exempt (IRB22-36266). | PMC10492874 | ||
Consent to participate | Informed consent was obtained from all individual participants included in the study. | PMC10492874 | ||
Consent to publish | All individual study participant data included in the manuscript has been anonymized. The manuscript contains no individual identifying details, images, or videos. | PMC10492874 | ||
References | PMC10492874 | |||
Background | depression, obsessive–compulsive disorder, anxiety, PCS neuropsychiatric symptoms | CORONAVIRUS DISEASE 2019, SYNDROME, DISORDERS | Shortly after the Coronavirus disease 2019 (COVID-19) pandemic, a considerable number of recovered patients reported persisting symptoms, especially neuropsychological manifestations, which were later named post-COVID syndrome (PCS). Immune dysregulation was suggested as one of the main mechanisms for PCS. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) that is mostly used to treat depression, anxiety disorders, and obsessive–compulsive disorder, has been suggested as an anti-COVID drug due to its anti-inflammatory effects, mainly through the sigma-1 receptor. Therefore, we aimed to evaluate fluvoxamine's effect on PCS neuropsychiatric symptoms. | PMC10064948 |
Method | infectious disease, dyspnea, fatigue | INFECTIOUS DISEASE, SECONDARY, INFILTRATES | In this double-blind randomized clinical trial, we included confirmed mild to moderate COVID-19 outpatients using polymerase chain reaction (PCR) by an infectious disease specialist. The presence of severe COVID-19 symptoms was evaluated by the infectious disease specialist and included dyspnea, SpO2 < 94% on room air, PaO2/FiO2 < 300 mm Hg, a respiratory rate > 30 breaths/min, and lung infiltrates > 50%. Then we performed permuted block randomization and assigned patients 1:1 into two groups to either receive fluvoxamine 100 mg tablet or a placebo daily for 10 days. Eligible patients were evaluated after 12 weeks for the presence of fatigue, as the primary, and other PCS symptoms as secondary outcomes. | PMC10064948 |
Results | Fatigue | We screened a total of 486 patients from March to June 2022. After 12 weeks, 42 patients receiving fluvoxamine and 43 patients receiving Placebo were evaluated for PCS. Patients had a mean age of 38.5 ± 14.1 and 48% of them were women. Fatigue was significantly lower in the fluvoxamine group ( | PMC10064948 | |
Conclusion | fatigue | We concluded that taking fluvoxamine during active COVID-19 can reduce the chance of fatigue but the advantage of fluvoxamine was not observed for other symptoms. Further studies are necessary to confirm these preliminary results. | PMC10064948 | |
Keywords | PMC10064948 | |||
Introduction | pneumonia, sleep disorders, fatigue, anxiety, inflammation, viral infection, microvascular thrombosis, infection, psychiatric, depression, obsessive–compulsive disorder | NEURODEGENERATION, PNEUMONIA, INFLAMMATION, DISEASE, VIRAL INFECTION, DISORDERS, INFECTION, CORONAVIRUS, PATHOLOGY, SEVERE ACUTE RESPIRATORY SYNDROME | In the last days of 2019, several cases of pneumonia of unknown etiology were reported to the World Health Organization (WHO) in Wuhan, China, which cause was confirmed to be of the Coronaviridae family a week later and is now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [In a systematic review of PCS symptoms, Nasserie et al. reported that 72.5% [55–80%] of COVID-19 patients had at least 1 persistent symptom after the initial disease. The most common symptoms were fatigue (median frequency of 40%) and sleep disorders (29.4%) [Several mechanisms have been suggested for PCS. Nalbandian et al. mentioned overlapping categories of severe systemic inflammation, microvascular thrombosis, neurodegeneration, and direct viral infection as possible underlying pathology of neuropsychiatric post-COVID symptoms. They proposed that chronic low-level inflammation in the brain and accumulation of memory T cells can lead to persistent effects of COVID-19 [Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is mostly used to treat depression, anxiety disorders, and obsessive–compulsive disorder [As mentioned above fluvoxamine has a probable influence on major pathways contributing to PCS neuropsychiatric symptoms, especially when taken in active disease, thus acting as a prophylactic agent for COVID-19 and PCS. Besides, its main effect as an SSRI can also lead to reduced stressors during infection, contributing to a lower chance of psychiatric problems after recovery [ | PMC10064948 |
Methods | PMC10064948 | |||
Design and participants | infectious disease, dyspnea | INFECTIOUS DISEASE, INFILTRATES | This randomized clinical trial (RCT) was conducted at Besat hospital, a major referral center east of Tehran, Iran. We enrolled patients above 18 years old with confirmed COVID-19 referring to the infectious disease clinic of the hospital. The confirmation of COVID-19 diagnosis was performed using polymerase chain reaction (PCR) by an infectious disease specialist. Only outpatients with primarily mild to moderate COVID-19 whose onset of symptoms was under 1 week were eligible. The presence of severe COVID-19 symptoms was evaluated by the infectious disease specialist and included dyspnea, SpO2 < 94% on room air, PaO2/FiO2 < 300 mm Hg, a respiratory rate > 30 breaths/min, and lung infiltrates > 50% [ | PMC10064948 |
Intervention | ADVERSE EFFECTS | Patients were randomized using permuted block randomization with blocks of 4, 6, and 8 then assigned 1:1 into two groups (A and B) to either receive fluvoxamine 100 mg tablet or a placebo daily orally for 10 days. We chose this regimen based on previous studies on the effect of fluvoxamine on COVID-19 patients and consultation with a local psychiatrist and pharmacologist about fluvoxamine’s adverse effects on the Iranian population who suggested a 100 mg daily dosage [ | PMC10064948 | |
Primary outcome | fatigue | SYNDROME | The primary outcome of our study was the presence of fatigue as the most common manifestation of the post-COVID syndrome [ | PMC10064948 |
Secondary outcomes | confusion, myalgia, sleep disorder, anxiety, vertigo, aggression, dizziness, memory impairment, headache, depression, distorted taste and smell | SECONDARY | The secondary outcome was the presence of other PCS neuropsychological manifestations which were also evaluated 12 weeks after enrollment. Patients were examined for symptoms including headache, vertigo, confusion, memory impairment, poor concentration, sleep disorder, aggression, anxiety, depression, myalgia, distorted taste and smell, and dizziness [ | PMC10064948 |
Statistical analysis | fatigue | The required sample size was calculated using a formula by Chow et al. for superiority trials. Using type I error rate of 0.05, 40% power, 15% margin, and expected proportion of 50% for fatigue, the primary outcome in both groups was due to having no prior information on the effect of fluvoxamine on fatigue [ | PMC10064948 | |
Results | PMC10064948 | |||
Demographics | We screened a total of 486 patients from March 2022 to Jun 2022, of which 329 patients did not meet inclusion criteria and 57 patients declined to participate in our study. We finally enrolled 100 patients, 50 patients were assigned to fluvoxamine and 50 to Placebo. At 12 weeks of follow-up, 85 patients were eligible for PCS evaluation (42 in fluvoxamine and 43 in Placebo), 9 discontinued medication and we were unable to contact 6 patients (Fig. Patients enrollment and follow-up flowchartPatients had a mean age of 38.5 ± 14.1 (39.8 ± 14 in fluvoxamine and 37.2 ± 14.3 in placebo) and 41 of the patients were women (20 in fluvoxamine and 22 in Placebo). Most of the patients received AstraZeneca (23, 13 in fluvoxamine and 10 in placebo) and Sinopharm (59, 28 in fluvoxamine and 31 in placebo) COVID-19 vaccine. No significant difference was observed between fluvoxamine and placebo groups in terms of baseline characteristics (Table Baseline characteristics of patients | PMC10064948 | ||
Secondary outcomes | depression | All other symptoms were less prevalent in patients taking fluvoxamine except for poor concentration (19% in fluvoxamine vs. 16.3% in placebo), Although none were significant. Most considerable one was depression (2.4% in fluvoxamine vs. 16.3% in placebo, | PMC10064948 | |
Discussion | shortness of breath, taste disorder, pneumonia, fatigue, infection, psychiatric, headache, depression, smell or | TASTE DISORDER, PNEUMONIA, DISEASE, INFECTION, ADVERSE EFFECTS | In this randomized clinical trial, we found out that fluvoxamine reduces the risk of developing fatigue, the most common complaint in PCS when taken during active COVID-19. As for other PCS neuropsychological manifestations, no significant differences were observed between fluvoxamine and placebo, albeit because our primary outcome was fatigue, this trial may not have the power to discuss the effect of fluvoxamine on other post-COVID symptoms.Although fluvoxamine has been suggested for COVID-19 treatment as early as 2020, to the best of our knowledge this is the first study regarding the effects of fluvoxamine during active infection on post-COVID symptoms [In a study only on COVID-19 outpatients, 53% of COVID-positive patients had persistent symptoms. The Main reported symptoms were fatigue (32%), smell or taste disorder (22%), and headache (12%). They also noted that the prevalence of long-term symptoms was similar during 3–5, 5–7, and 7–10 months after the initial disease [There are several studies on the effect of fluvoxamine but only on COVID-19 severity during initial infection. In 2020 Lenze et al. conducted an RCT on mild COVID-19 patients receiving 300 mg/day of fluvoxamine or placebo for 15 days, evaluating clinical deterioration (shortness of breath or hospitalization for shortness of breath or pneumonia and oxygen saturation less than 92% or need for supplemental oxygen). Clinical deterioration didn’t occur in patients taking fluvoxamine and they had a lower incidence of adverse effects [It is noteworthy to mention that the effect of fluvoxamine on depression can be the result of two separate pathways. First the direct effect of fluvoxamine on serotonin levels as an SSRI, and second its probable anti-inflammatory role to prevent post-COVID psychiatric symptoms. We believe that in our study the lower prevalence of depression in patients taking fluvoxamine majorly resulted from the second pathway. The reason for this assumption is that based on the literature, fluvoxamine usually takes 4–6 weeks to effectively treat depression and the duration of the fluvoxamine regimen was 10 days in this trial [ | PMC10064948 |
Limitations | fatigue | SECONDARY | Our study has several potential limitations. First, although conducted in a major referral center, this is a single-center study only on the Iranian population with a relatively small sample size, therefore our findings should be regarded as preliminary. Second, due to worldwide COVID-19 vaccination, future candidates for this drug will probably be vaccinated, patients. In addition, at the time this study was conducted most Iranians received COVID-19 vaccination, therefore there was a very small number of patients who weren’t vaccinated. Thus, we only included patients who had received at least 2 doses of the COVID-19 vaccine to remove this disparity. Consequently, the result of our study may not apply to non-vaccinated patients. Finally, patients in the fluvoxamine group, received a fixed dose of 100 mg/day and higher doses may have a different impact on PCS, thus further studies are required to evaluate the optimal dosage of fluvoxamine. We believe our biggest limitation is the small sample size due to our limited budget, which reduced the power of this study to support the suggested hypothesis and make our study a preliminary and pilot study. We should also mention that because the primary outcome of this study was fatigue, it doesn’t have the power to support finding on other neuropsychological symptoms, our secondary outcomes. | PMC10064948 |
Acknowledgements | We acknowledge all healthcare workers involved in diagnosing and treating patients in Besat Hospital. | PMC10064948 | ||
Authors’ contributions | A. Ajam contributed to interpreting the data, draft writing, and final editing. A. Ranjbar Naeini contributed to research design and final editing. R. Hamidi Farahani contributed to the research design and revised it critically. The author(s) read and approved the final manuscript. | PMC10064948 | ||
Funding | All funding support was provided by the AJAUMS. | PMC10064948 | ||
Availability of data and materials | The dataset generated and analyzed in this study are available from the authors upon reasonable request. Please contact ali.ajam@outlook.com. | PMC10064948 | ||
Declarations | PMC10064948 | |||
Ethics approval and consent to participate | Informed consent was obtained from all study participants. The protocol of this study is by the 2013 Helsinki declaration and was approved by the Ethics Committee of AJA University of Medical Sciences (AJAUMS), Ethics ID: IR.AJAUMS.REC.1400.302. This RCT was registered in the Iranian registry of clinical trials (IRCT), a primary registry in the WHO registry network (registration number: IRCT20220526054990N1) on 01/06/2022. | PMC10064948 | ||
Consent for publication | Not applicable. | PMC10064948 | ||
Competing interests | The authors declare no competing interests. | PMC10064948 | ||
References | PMC10064948 | |||
Background: | Parkinson’s disease, PD | Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson’s disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. | PMC10578294 | |
Objective: | PD | To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. | PMC10578294 | |
Methods: | Parkinson Disease, PD | PARKINSON DISEASE | As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives’ input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. | PMC10578294 |
Results: | cognitive, disability | DISEASE PROGRESSION, DISEASE | An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. | PMC10578294 |
Conclusion: | PD | We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges. | PMC10578294 | |
INTRODUCTION | Parkinson Disease, Parkinson’s disease, PD | PARKINSON DISEASE | There is currently no proven intervention to delay the progression of Parkinson’s disease (PD). A number of novel and promising treatment approaches are being developed to address this and need to be tested in clinical trials. Multi-arm, multi-stage (MAMS) platform trials may help accelerate the identification of potentially successful treatments by improving efficiency of the clinical trial process. MAMS trials evaluate multiple agents simultaneously against a shared placebo arm and allow the addition of new arms as well as cessation of ineffective treatments at interim stages. However, there is no current consensus on the most appropriate outcome measures (OM) for disease-modifying trials in PD to be included in such an approach.The Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative aims to accelerate the identification of disease-modifying treatments for PD through a MAMS platform trial approach. An important component of this novel approach is the identification and selection of appropriate outcome measures, suitable for inclusion across several different study arms as well as meeting the overarching aim. Here, we present an inventory of outcome measures based on current evidence and make initial recommendations for their potential inclusion as core, supplementary (depending on study arm) or exploratory outcome measures in such trials.This inventory of potential outcome measures for use in disease-modifying trials is based on a consensus effort by an expert group with strong patient and public engagement input. The group used information from literature reviews, other existing and ongoing efforts, and discussion with regulatory bodies and group discussions. Particular consideration for inclusion in the inventory was given to clinically relevant outcome measures that are meaningful to patients, align with regulatory expectations and provide data to support adoption in larger healthcare systems. For future adaptation according to emerging new evidence, a framework was also created for evaluation and inclusion of outcome measures of potential relevance in the future, including clinical outcome measures, biomarkers, and novel measurement technologies. | PMC10578294 |
DISCUSSION | PD | We here present an up-to-date inventory of outcome measures for disease-modifying trials in PD based on expert and PPIE consensus. This inventory and framework will be used to guide the decision to select the outcome measures of the EJS ACT-PD MAMS platform trial, based on their fulfilment of desired criteria for an endpoint (e.g., validated, reliable, sensitive to change, acceptable) and their relevance to the intervention based on its mechanism of action and previously known effects (e.g., wet biomarkers as surrogate or direct markers of target engagement). When selecting and classifying the above measures as Core, Supplemental and Exploratory, a compromise had to be made between measures with the best clinimetric properties, acceptability to patients, feasibility, previous experience of use in PD trials, and regulatory considerations, which potentially might have led to prioritizing measures which appear less “promising” from a purely theoretical point of view (i.e., original validation study results) over others, to achieve an adequate balance and provide a realistic and practical tool. This work could also inform other trial initiatives aiming to identify disease-modifying treatments for PD and the framework used will allow updates with new emerging evidence in the future. However, this inventory of outcome measures was created as part of the development of a MAMS trial for progression of PD and as such, presents some particularities which might have influenced the final list of included outcomes. This type of trial requires large participant numbers across a variety of centers, and has a much longer duration than usual randomized controlled trials (RCTs) (i.e., several years) [Despite being included as exploratory due to the lack of formal validation in this setting, novel outcome measures, and especially digital endpoints, are a promising alternative to complement the currently available instruments. Their potentially increased sensitivity and the possibility of continuous monitoring in real-life conditions (i.e., at home) is likely to be a valuable addition to the administration of scales in the clinical setting. In line with this, a number of initiatives are looking into the clinical validity of these endpoints and their implementation in clinical research [The main strength of our approach was strong expert and PPIE consensus, embedding the patient’s voice into the development and recommendation of outcome measures, as well as evidence from literature reviews, information from other initiatives, and input from regulatory bodies. | PMC10578294 | |
Conclusions | PD | With the above methodology, we have identified a broad range of outcome measures which can be potentially included in disease-modifying PD trials, and make recommendations for their inclusion as core, supplementary (for specific arms) and exploratory measures in the EJS ACT-PD MAMS initiative. For other MAMS initiatives, this review aims to serve as a resource from which to select the desired outcome measures according to the requirements of the study (e.g., population, mechanism of action of the intervention, etc.). We also provide a framework for future update of the evidence on outcome measures in disease-modifying PD trials. | PMC10578294 | |
EJS ACT-PD CONSORTIUM MEMBERS | Additional EJS ACT-PD consortium members (further details are provided in the | PMC10578294 | ||
Supplementary Material | PMC10578294 | |||
Supplementary Material 1 | Click here for additional data file. | PMC10578294 | ||
Supplementary Material 2 | Click here for additional data file. | PMC10578294 | ||
ACKNOWLEDGMENTS | Parkinson’s Disease | This work was done as part of the Edmond J Safra Accelerating Clinical Trials in Parkinson’s Disease (EJS ACT-PD) Initiative, which is funded by the Edmond J Safra Foundation. | PMC10578294 | |
SUPPLEMENTARY MATERIAL | The supplementary material is available in the electronic version of this article: | PMC10578294 | ||
CONFLICT OF INTEREST | Nordisk, MTH, Parkinson’s Research Committee member, NINDS, BBS, Parkinson’s disease, PD, Parkinson’s, MDS COA | SECONDARY, FOUNDER, BRAIN | RSW has received speaking honoraria from GE Healthcare and a writing honorarium from Britannia. DVW reports consultancy and speaker fees from Bial and Britannia. MTH received payment for Advisory Board attendance/consultancy for Lundbeck, ESCAPE Bio, Evidera, Manus Neurodynamica, Biogen MA, CuraSen Therapeutics, Roche Products Ltd. MTH is an advisory founder of NeuHealth Digital Ltd (company number: 14492037), a digital biomarker platform to remotely manage condition progression for Parkinson’s.AJ has been involved in the development and clinical assessment of a smartphone-based tool for Parkinson’s disease (cloudUPDRS). ML received fees for advising on a secondary analysis of a Parkinson’s RCT (GDNF) sponsored by North Bristol NHS trust.AN has been involved in the development of the Bradykinesia-Akinesia Incoordination (BRAIN) test. AN is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review.HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). CBC has received personal fees from AbbVie, Bial, Scient, Orkyn, Abidetex, UCB, Pfizer, EverPharma, Lundbeck, Global Kinetics, Kyowa Kirin, Britannia, and MedScape; and appointments as a Cure Parkinson’s Linked Clinical Trials (LCT) committee member, a Cure Parkinson’s Research Committee member, and a Parkinson’s UK College of Experts Panel member. CBC is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. TF has served on Advisory Boards for Peptron, Voyager Therapeutics, Handl therapeutics, Gain therapeutics, Living Cell Technologies, Abbvie, Bluerock, Bayer & Bial. TF has received honoraria for talks sponsored by Bial, Profile Pharma, Boston Scientific & Novo Nordisk. TF is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. AS is a member of the MDS-UPDRS Development Group, the MDS-NMS Development Group, the NINDS CDE QoL Group, the MDS Rating Scales Review Committee, and the MDS COA Early and Prodromal PD Working Group. AS has been involved in the development of the MDS-UPDRS, the MDS-NMS, and the PQoL.AS reports consultancy fees from Biogen, Abbvie, Roche, Bial, and GE Healthcare; license fees from University College London; and royalties from Oxford University Press. CGR, MB, MBu, CSC, BH, CL, GM, PP, KP, LR, CS, CWG and MLZ have no conflict of interest to report. | PMC10578294 |
DATA AVAILABILITY | Data sharing is not applicable to this article as no datasets were generated or analyzed during this study. | PMC10578294 | ||
ADDITIONAL STATEMENT | For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission. | PMC10578294 | ||
REFERENCES | PMC10578294 | |||
Subject terms | An HPMC-based nasal spray solution containing human IgG1 antibodies against SARS-CoV-2 (nasal antibody spray or NAS) was developed to strengthen COVID-19 management. NAS exhibited potent broadly neutralizing activities against SARS-CoV-2 with PVNT | PMC10511465 | ||
Introduction | SARS-CoV-2 infections | VIRUS, SARS-COV-2 INFECTION, SARS-COV-2 BREAKTHROUGH INFECTION | The enduring waves of SARS-CoV-2 breakthrough infections create a global impediment that requires additional measures beyond vaccination to mitigate this perpetual situation. SARS-CoV-2 is an RNA virus with the characteristic of multiple spike glycoproteins on its envelopeNasal Antibody Spray (NAS) is an HPMC-based nasal spray solution containing human IgG1 antibodies. It has been approved by the Thai FDA as an innovative medical device platform (Class 4) to support mucosal immunity against SARS-CoV-2 infections via a dual mechanism of action through antibody-mediated specific inhibition coupled with a steric barrier (Fig. Mechanism of action of NAS. NAS provides the dual-action physical barrier on nasal mucosa by (1) forming of steric barrier at the cell surface by HPMC and (2) inhibiting SARS-CoV-2 viral particles via an anti-SARS-CoV-2 human IgG1 antibody cocktail. This figure was created with BioRender.com. | PMC10511465 |
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