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Funding

Open Access funding enabled and organized by Projekt DEAL. Application for funding by the German Research Foundation (DFG) is ongoing.

PMC9949689

Availability of data and materials

It is possible to make the full protocol, participant-level dataset and statistical code available on the basis of a reasonable request.Patient and public involvement: There was no public or patient involvement in the design of the protocol.

PMC9949689

Declarations

PMC9949689

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Medical Faculty of the Ludwig-Maximilians University of Munich (project number 020–798). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written, informed consent to participate will be obtained from all participants.

PMC9949689

Consent for publication

All authors gave final approval and agreed to be accountable for all aspects of the work. All authors contributed equally to the project conception, the development of the study design and the writing of the manuscript.

PMC9949689

Competing interests

The authors declare that they have no competing interests.

PMC9949689

References

PMC9949689

1. Introduction

fracture, fractures, Fractures

ADVERSE EVENTS

Background and Objectives: Fractures of the proximal humerus are common, particularly in elderly populations. Anatomical locking plates target stabilization with a multitude of screws spanning into the humeral head. Sound implant placement and screw length determination are key for a successful clinical outcome but are difficult to obtain from planar X-rays. A novel implant positioning technology for proximal humerus plating (Xin1) outputs screw lengths suggestions and plate position based on hole projections in conventional X-ray images. This study investigated the performance of a prototype Xin1 system in a postmortem (in vitro) experiment as well as in a clinical handling test. Materials and Methods: For in vitro testing, twelve shoulders from six anatomical specimens were randomized into two groups to compare the Xin1 technique to the conventional operation in terms of surgical precision, procedure time and X-ray exposure. For the clinical trial, 11 patients undergoing plating of the proximal humerus were included. The aim was to investigate clinical handling of the Xin1 marker clip and to retrospectively evaluate the system performance in a real-life fracture situation. Image pairs before and after insertion of the proximal screws were retrospectively processed to investigate the influence of potential bone fragment shifts on the system output. Results: In the postmortem experiment, the use of the system significantly improved the surgical precision (52% error reduction), procedure time (38% shorter) and radiation exposure (64% less X-rays). Clinical handling demonstrated seamless embedding of the marker clip into existing clinical workflows without adverse events reported. Retrospective X-ray analysis on six eligible patients revealed differences in the calculated screw lengths of ≤2 mm before and after screw insertion for five patients. In one patient, the screw lengths differed up to 8 mm, which might indicate displacement of the head fragment. Conclusions: Results suggest a strong potential of the Xin1 assistance technology to enhance the surgical procedure and patient outcomes in the rising incidence of osteoporotic humeral fractures. Robust performance in a real-life fracture situation was observed. In-depth validation of the system is, however, needed before placing it into clinical practice.Proximal humerus fractures are among the most common injuries [Adequate plate positioning [We recently proposed a simple and generic tracking technology (Xin1—Implant Positioning Assistance) utilizing conventional radiographic images to determine 3D positions and orientations of implants, instruments and anatomy [The purpose of this study was (1) to assess the performance of the Xin1 system for application at the humerus in comparison to the manual procedure in terms of accuracy, X-ray exposure and procedure time in a postmortem study; and (2) to investigate performance and handling of the system in a clinical fracture situation by retrospectivly comparing the system output before and after screw insertion as a measure for the influence of potential bone fragment shifts.

PMC10055017

2. Materials and Methods

PMC10055017

2.1. Xin1 System

The Xin1 technology is a generic, X-ray-based tracking and navigation concept, designed to assist implant positioning in various orthopedic applications. The underlying principle is based on feature extraction from projections of cylindrical holes in X-ray images for determining the spatial alignment of the implant and anatomy. It was first described by Windolf et al. [For proximal humeral plating, a stainless-steel marker comprising three cylindrical holes arranged in a defined pattern and two polymer clamps is clipped on a drill sleeve which is attached to a conventional anatomic locking plate (PHILOS ref: 441.901, DePuy Synthes Inc., Raynham, MA, USA) (

PMC10055017

2.2. In Vitro Study

CORTEX

For performance assessment, the Xin1 system was compared to the conventional free-hand method in 12 intact, non-fractured shoulders from 6 formalin-embalmed, full-body specimens (3 male and 3 female), which were pre-used for medical student courses. The experiment was performed at the Department of Anatomy of the Medical University of Innsbruck, Austria. Left and right shoulders were randomized into Xin1 and conventional groups. All operations were performed by a single operator (DK), who was at the time the resident surgeon with moderate surgical experience. For both groups, a deltopectoral approach was created and a PHILOS plate was prepositioned and fixed with a cortex screw in the elongated combi-hole (F-level, For the conventional procedure, the plate position and screw lengths were estimated via repeated fluoroscopy and by use of a length probe (Ref. 03.122.052, DePuy Synthes Inc., Raynham, MA, USA) with a target TJD of 5 mm. Eight screws (Ref. X12.1xx, 3.5 Locking Screw, TAN, DePuy Synthes Inc., Raynham, MA, USA) were placed using the screw insertion guide (Ref. 03.122.053, DePuy Synthes Inc., Raynham, MA, USA). Only screw hole 7 on the D-level was left empty. Plate and screw placement was verified via fluoroscopic imaging.For the Xin1 procedure, a marker clip was additionally attached to the drill sleeve (For the TJD accuracy measurement, the humeral head was dislocated from the joint, and the screw tip-to-joint distances were measured including the cartilage layer for all screws by inserting a K-wire into the over-drilled hole until touching the screw tip. The insertion depth was then marked with forceps and measured with a caliper (Non-parametric independent sample tests (Mann–Whitney U) were performed to compare both techniques regarding accuracy (TJD and TJD error), procedure time, number of fluoroscopic images and radiation time. All analyses were performed using SPSS software version 27 (IBM Corporation, Armonk, NY, USA). For all tests level of significance was set to α = 0.05.

PMC10055017

2.3. Clinical Handling Test

fracture

Eleven patients undergoing plate fixation osteosynthesis with PHILOS were enrolled in a focused registry at a single medical center (UZ Leuven, Leuven, Belgium). The clinical trial was approved by the local ethical committee and the Federal Agency for Medicines and Health Products Belgium (FAMHP, AFMPS/SE/80M0661) and was registered at clinicaltrials.gov (NCT03427112). Informed consent was obtained from all participants before surgery. The standard surgical protocol was maintained, except for attaching an Xin1 marker clip after plate prepositioning. The marker clip was manufactured from medical-grade stainless steel and PEEK (Polyetheretherketon) and was designed for reuse in a standard hospital surgical instruments workflow including autoclaving and cleaning. Intraoperative X-rays from two stages, before and after screw placement, were stored in a DICOM (Digital Imaging and Communications in Medicine) format and were retrospectively evaluated with the Xin1 software. No system feedback was provided to the surgeon during operation. Placed screw lengths during surgery were noted for all operations.Image pairs from both stages were formed from the available X-rays and processed with the Xin1 software. An image pair was found valid if the view angle between the images exceeded 15°. So that several valid pairs could be formed, the pair with the largest view angle was selected. Screw lengths and plate positions were computed from the selected pairs for both stages. The plate position is calculated in relation to the anatomy, defined as the offset of the calculated center of the humeral head from the central screw trajectory (screw 7, D-Level) in cranial–caudal and dorsal–ventral directions (To investigate the effect of potential head displacement during screw insertion in a real fracture situation, the differences in screw length before and after fixing the plate with screws (Statistically, correlation analysis was performed on the computed screw lengths before screw insertion and the actually placed screw lengths by pooling the patients and calculating Pearson’s correlation coefficient R.

PMC10055017

3. Results

PMC10055017

3.1. In Vitro Study

perforations

The mean procedure time for the conventional technique was 35:03 ± 6:11 min (mean ± SD), compared to 21:41 ± 4:31 min for the Xin1 technique. This total time reduction of 38% when using Xin1 was statistically significant (The number of fluoroscopic images was on average 30.3 ± 5.7 (mean ± SD) with the conventional technique and 10.8 ± 2.5 images with Xin1. This reduction of 64% when using the Xin1 system was statistically significant (In each study group 48 screws were placed. Two joint perforations occurred in the conventional groups, while in the Xin1 group no perforations were observed. The mean tip–joint distance (TJD) was 5.8 ± 2.6 mm (mean ± SD) with the conventional technique, and 5.1 ± 1.3 mm when using Xin1 (

PMC10055017

3.2. Clinical Handling Test

proximal humerus fractures, Fracture

ADVERSE EVENTS

Eleven proximal humerus fractures (eight left, three right shoulders) from eight female and three male patients were operated by five different surgeons. The average age of patients at surgery was 67 years and ranged between 47 and 84 years. Fracture types (AO classification) were: 1× 11A2, 1× 11A3, 3× 11B1, 1× 11B2, 4× 11C1 and 1× 11C3. With one exception, where a Philips Zenition 70 system (Koninklijke Philips N.V., Amsterdam, The Netherlands) was used, all intraoperative images were acquired with a Siemens Arcadis Varic (Siemens Healthcare GmbH, Erlangen, Germany) C-arm. Handling of the marker clip in the hospital environment and during surgery was feasible in all patients and did not interfere with hospital processes or surgical procedures. No adverse events concerning the use of the marker clip were recorded for the 11 performed operations. For the retrospective image analysis, five out of eleven patients needed to be excluded for various reasons: for example, one patient was excluded due to the intraoperative use of a wrong drill sleeve, leading to the mispositioning of the marker clip. For two patients, no images after screw insertion were stored to the C-arm. For another two patients, the image pair view angle was too narrow for calculation.Xray images of the remaining six patients underwent retrospective evaluation. Robust marker detection, humeral head segmentation and screw length determination were achieved in all image pairs. The view angle between the images of a pair was on average 27° (range 19°–34°). The calculated screw lengths before and after screw placement differed on average by 1.2 ± 1.7 mm. In five out of six patients, this difference was ≤2 mm for all screws. In one patient (#10), differences up to 8 mm were found. A total of thirty-seven screws were placed in the six evaluated patients. Used screw lengths ranged from 32 to 50 mm. The Xin1 calculation before screw placement correlated significantly with the actual screw lengths implanted (R = 0.78, Maximum plate offset before screw placement was 5 mm in a dorsal–ventral direction and 9 mm in a cranial–caudal direction in respect to the center of the humeral head. After placing the screws, the relative plate position shifted at a maximum of 4 mm for five out of six patients. In one patient (#10), the plate was displaced by 10 mm in the dorsal–ventral direction after screw placement according to the Xin1 measurement (

PMC10055017

4. Discussion

fracture, fractures

ADVERSE EVENTS, STILL

The Xin1 implant positioning system, as introduced in [Anatomical locking plates such as the PHILOS system stabilize proximal humerus fractures by spanning a multitude of screws in the often-osteoporotic head segment. It is aimed to anchor the screw tips in the subchondral bone region, close to the cartilage layer. The task is surgically demanding due to an eminent risk of screw penetration into the joint space while trying to judge an oblique screw path inside a spherical anatomical structure from planar X-ray projections. On the other hand, too-short screws miss anchorage [In the scope of this work, the prototype Xin1 system was evaluated in terms of performance in both postmortem and clinical settings. The system estimates the plate position and calculates all required screw lengths to reach into the subchondral bone area from a pair of conventional C-arm images. Xin1 outperformed the conventional freehand technique in terms of surgical precision (52% error reduction), procedure time (38% shorter) and radiation exposure of OR personnel and the patient (64% less X-rays). Particularly for medical professionals, the continuous exposure to ionizing radiation during surgery is a frequently addressed problem [The postmortem experiment was performed on full-body specimens with compromised soft tissue mantle due to embalmment and previous use. However, we believe that the experiment carried high relevance for judging the technology before entering into clinical testing. One methodological issue, though, could not be neglected, which was the absence of bone fractures. In a second phase, we hence conducted a clinical registry on fracture patients to investigate the potential effect of bone fragment shifts on the system output, and at the same time to analyze the clinical handling of the Xin1 marker clip. Safe handling was shown in all 11 included patients by the absence of device-related adverse events. To minimize risks to the patient at the current state of system development by potentially falsified system outputs, X-ray image analysis was performed in a retrospective fashion without providing system information to the operator during surgery. The missing feedback in the operating theatre reduced risks but also led to a high number of patients, who needed to be excluded from the image-based evaluation (five out of eleven). These dropouts are deemed to be artifacts from the retrospective study design and may be avoided in the future when real-time feedback is provided to the operator. A stereotactic system always relies on an angular spread of at least two view ports to reconstruct a 3D situation [Besides these general observations, the clinical study confirmed the feasibility of the marker clip to be embedded into hospital and surgical workflows. The system software demonstrated robust performance in presence of real-life bone fractures. Certain head fragment shifts due to manipulations during the screw insertion were suggested by differences in the computed screw lengths and measured plate position before and after screw insertion. Shifts were generally small, but in one case they reached 10 mm in the dorsal–ventral direction. Clinical consequences such as screw perforation into the joint cannot be excluded in such cases. It is therefore proposed to perform a verification measurement with the Xin1 system after the head fragment has been fixed in place with the first screw. On a critical note, it cannot be ruled out that the measured differences are artifacts related to inaccuracies of the system rather than describing actual bone fragment shifts. In this regard, the segmentation procedure to determine the position of the humeral head, still relying on user input, might play an important role. Inaccurate determination of the humeral head boundaries will impact the accuracy of the system. Fully automated segmentation may be desired in the future. In a previous bench experiment [Study limitations are summarized as the following: The postmortem experiment was performed on unfractured embalmed body donors with compromised soft tissues. The effect of intact soft tissues and fractured proximal humerus was hence difficult to estimate from this sub-study. Furthermore, the tip–joint distance evaluation assumed a constant cartilage layer thickness, which naturally varies between locations and individuals. Procedure time assessment did not take system setup and takedown durations into account, and thus represents only a net value. The clinical registry allows only for preliminary conclusions at this early development stage because of the missing system feedback in the operating room. This also led to a considerable number of dropouts lowering the sample size for image evaluation. As desired for a clinical handling investigation, several surgeons shared the surgeries. This, on the one hand, gave valuable insights about marker clip usage in different hands, but might have contributed to the large number of excluded datapoints for image analyses. However, several confounders regarding the Xin1 approach for proximal humerus plating could be identified from the studies, including: potential marker movements, risk for use of wrong implants and instruments, omitted use of a screw guide, bone fragment shifts due to surgical manipulation, a too-narrow X-ray view angle or the segmentation procedure of the humeral head requiring manual interaction. Furthermore, some technical limitations rendering validation and regulation of such assistance devices difficult are to be mentioned. Optical image distortion of older image intensifiers can drastically influence the system accuracy. Flat panel-based C-arms solve this issue and currently replace image intensifiers around the globe. Still, interfacing to the imaging modalities remains an issue. A variety of analog and digital output protocols make connecting external devices difficult. Important parameters such as flip or rotation flags are not transmitted. The ability to run third party image processing software directly on the C-arm would be an important prospect for future developments, dramatically increasing usability and effectiveness of assistance technologies such as Xin1.

PMC10055017

5. Conclusions

fracture, fractures

This study demonstrated the potential of a newly proposed assistance technology for implant positioning in proximal humerus plating using conventional X-ray projections. In an in vitro setting, the system significantly improved surgical precision, reduced X-ray exposure and shortened surgery time. In a clinical handling test, the device demonstrated seamless embedding into existing clinical workflows and robust performance in a real-life fracture situation. However, certain issues crystallized and need to be addressed before placing such system into clinical practice. A strong potential to improve patient outcomes in the rising incidence of osteoporotic humeral fractures is eminent.

PMC10055017

Author Contributions

D.K., S.N.

Conceptualization, M.W.; methodology, M.W. and J.B.; software, M.W.; formal analysis, M.W. and J.B.; investigation, M.W., D.K., S.N. and A.S.; writing—original draft preparation, M.W. and J.B.; writing—review and editing, R.G.R., D.K. and M.B.; visualization, M.W. and J.B.; supervision, M.B. and R.G.R.; project administration, M.W.; funding acquisition, M.W. All authors have read and agreed to the published version of the manuscript.

PMC10055017

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Federal Agency for Medicines and Health Products Belgium (FAMHP, AFMPS/SE/80M0661, 6 March 2017).

PMC10055017

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

PMC10055017

Data Availability Statement

Not applicable.

PMC10055017

Conflicts of Interest

The authors declare no conflict of interest.

PMC10055017

References

Postmortem experiment. (User interface of the Xin1 software for proximal humeral plating showing the semi-automatically selected humeral head (red circle) and the resulting virtual screw trajectories (green lines). All screw lengths are shown on the left side of the graphical user interface. Left image shows screw length determination after plate prepositioning and right after final screw insertion. Graphical user interface by MeVis BrestCare GmbH.Xin1 software output for an exemplary patient. Top row: image pair before screw insertion. Calculated screw trajectories depicted in green. Segmented humeral head in red. Bottom row: image pair after screw insertion (verification images). Green trajectories coincide with inserted screws.Procedure time for the conventional method versus Xin1 for three phases during the operation and in total time.Number of X-ray images taken for conventional and Xin1 groups for three phases during the operation and in total.Precision of achieved tip–joint distance (TJD). Target distance was set to 5 mm in Xin1 (red line). In total, 48 screws were placed in 6 human specimens.Correlation between Xin1 computed screw lengths (before screw placement) and actually placed screw lengths (no system output provided to the surgeon).Intraoperative X-ray of one case with tilted screws (PHILOS A-level) as apparent by non-alignment with the calculated screw trajectories (green lines).Patient details, view angle of image pairs and plate position before (pre) and after (post) screw placement for the 6 patients undergoing retrospective image evaluation. D–V: dorsal–ventral plate position; negative sign: head center is located ventral from plate. C-C: cranial-caudal plate position; negative sign: head center is located caudal from plate. f: female, m: male; L: left, R: right.

PMC10055017

Introduction

Ravulizumab demonstrated efficacy and an acceptable safety profile versus placebo in the randomized controlled period (RCP) of the phase 3 CHAMPION MG trial in patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. We report an interim analysis of the ongoing open-label extension (OLE) designed to evaluate long-term treatment effects.

PMC10134722

Methods

Myasthenia Gravis

MYASTHENIA GRAVIS

Following completion of the 26-week RCP, patients could enter the OLE; patients who received ravulizumab in the RCP continued the drug; patients who previously received placebo switched to ravulizumab. Patients receive body-weight-based maintenance dosing of ravulizumab every 8 weeks. Efficacy endpoints up to 60 weeks included Myasthenia Gravis–Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores, with least-squares (LS) mean change and 95% confidence intervals (95% CI) reported.

PMC10134722

Results

EVENTS, MENINGOCOCCAL INFECTIONS

Long-term efficacy and safety in the OLE were analyzed in 161 and 169 patients, respectively. Improvements in all scores were maintained through 60 weeks in patients who received ravulizumab during the RCP; LS mean change from RCP baseline in MG-ADL score was − 4.0 (95% CI: − 4.8, − 3.1; p < 0.0001). Rapid (within 2 weeks) and sustained improvements occurred in patients previously receiving placebo; LS mean change in MG-ADL score from OLE baseline to Week 60 was − 1.7 (95% CI: − 2.7, − 0.8; p = 0.0007). Similar trends were seen in QMG scores. Ravulizumab treatment was associated with a decreased rate of clinical deterioration events compared with placebo. Ravulizumab was well tolerated; no meningococcal infections were reported.

PMC10134722

Conclusion

Findings support the sustained efficacy and long-term safety of ravulizumab, administered every 8 weeks, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis.ClinicalTrials.gov identifier: NCT03920293; EudraCT: 2018-003243-39.

PMC10134722

Supplementary Information

The online version contains supplementary material available at 10.1007/s00415-023-11699-x.

PMC10134722

Keywords

Open Access funding enabled and organized by Projekt DEAL.

PMC10134722

Introduction

anti-AChR

Myasthenia gravis (MG) is a rare, chronic, autoimmune condition that affects the neuromuscular junction [Approximately 85% of patients with gMG have autoantibodies directed against the acetylcholine receptor (AChR) [Traditional therapies for MG include oral cholinesterase inhibitors and long-term immune therapies, such as corticosteroids and non-steroidal immunosuppressants (including azathioprine, mycophenolate mofetil, cyclosporin, and tacrolimus) [We have previously reported data from the phase 3, randomized, placebo-controlled CHAMPION MG study showing that ravulizumab is well tolerated and improves clinical outcomes compared with placebo in patients with anti-AChR antibody-positive gMG [

PMC10134722

Methods

PMC10134722

Study design and patients

anti-AChR, Myasthenia Gravis

MENINGOCOCCAL INFECTION, DISEASE, MYASTHENIA GRAVIS

The CHAMPION MG study consists of a 26-week, double-blind, randomized, placebo-controlled period (RCP), followed by an ongoing OLE of up to 4 years (Fig. Study design. IV, intravenous. From NEJM Evidence, Vu T, et al, Terminal complement inhibitor ravulizumab in generalized myasthenia gravis, 1, EvidDoa2100066. Copyright © 2022 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical SocietyAdult patients (≥ 18 years of age), diagnosed with MG ≥ 6 months before screening and who were anti-AChR antibody-positive, were included in the study. Additionally, patients had to have Myasthenia Gravis Foundation of America class II–IV disease and a Myasthenia Gravis–Activities of Daily Living (MG-ADL) total score of ≥ 6 at screening and randomization. As patients treated with C5 inhibitors are at increased risk of meningococcal infection, all participants were required to be vaccinated against

PMC10134722

Treatments

During the RCP, patients were randomized 1:1 to intravenous ravulizumab or matching placebo. Ravulizumab dosing during the study was based on patients’ body weight. In the RCP, patients received an initial loading dose of 2400, 2700, or 3000 mg on Day 1, followed by a maintenance dose of 3000, 3300, or 3600 mg starting on Day 15 and every 8 weeks thereafter. On completing the RCP, patients were invited to enter the OLE, which started for each patient when he or she received a dose of ravulizumab at Week 26 of the study. The doses and dosing schedule at the start of the OLE were designed to ensure that patients and study personnel remained blinded to the treatment assignment in the RCP. Therefore, at Week 26, patients who had received ravulizumab during the RCP (ravulizumab–ravulizumab group) received ravulizumab 900 mg, and patients who had received placebo (placebo–ravulizumab group) received a body-weight-based loading dose of 2400, 2700, or 3000 mg. For the next scheduled maintenance dose at Week 28 and every 8 weeks thereafter for up to 4 years, all patients received body-weight-based doses of 3000, 3300, or 3600 mg.Patients receiving stable therapy with cholinesterase inhibitors and immunosuppressants at the start of the study could continue them. Dose changes were not permitted during the RCP, but were allowed during the OLE at the investigator’s discretion. Rescue therapy, including high-dose corticosteroids, plasma exchange, or intravenous immunoglobulin, was permitted throughout the study for patients experiencing clinical deterioration.

PMC10134722

Study endpoints

weakness, Neuro-QoL Fatigue, fatigue

NEUROLOGIC DISORDERS, ADVERSE EVENTS, DOUBLE VISION, ADVERSE EVENT, EYELID DROOP

Efficacy was evaluated using the following validated measures: the MG-ADL score [The MG-ADL scale is an 8-item survey of patient-reported MG symptom severity with a total score range of 0–24. The QMG is a 13-item clinician assessment of strength with a total score range of 0–39. The MG-QOL15r is a 15-item questionnaire on health-related quality of life with a total score range of 0–30. The Neuro-QoL Fatigue subscale evaluates the effect of fatigue on the quality of life of patients with neurologic disorders. The long form of the subscale used in this study comprises 19 patient-reported items with a total score range of 19–95. For each of the four measures, a reduction in scores indicates an improvement.MG-ADL and QMG were assessed at screening, baseline, and Weeks 1, 2, 4, 10, 12, 18, and 26 of the RCP, and at Weeks 28, 30, 36, 38, 44, 52, and 60 during the OLE. MG-QOL15r and Neuro-QoL Fatigue subscale scores were assessed at baseline and Weeks 4, 12, 18, and 26 of the RCP, and at Weeks 30, 38, 44, 52, and 60 during the OLE. At each assessment, the order of endpoints assessed was MG-ADL, QMG, MG-QOL15r, and Neuro-QoL Fatigue. Administration of the MG-ADL questionnaire and QMG and MG-QOL15r assessments was performed by trained clinical evaluators; preferably the same person evaluated each patient throughout the study. Assessment of QMG was performed at approximately the same time of day at each scheduled visit if possible. Patients who were receiving a cholinesterase inhibitor during the RCP or OLE were required to refrain from taking it for at least 10 h before each scheduled assessment.Study endpoints were change from RCP or OLE baseline in MG-ADL, QMG, MG-QOL15r, and Neuro-QoL Fatigue scores. The primary endpoint was change in MG-ADL score at Week 60. In addition, a responder analysis of MG-ADL and QMG scores was performed, with a clinical response defined as an improvement from baseline of ≥ 3 points for MG-ADL or ≥ 5 points for QMG. Occurrence of clinical deterioration and the use of rescue therapy by patients experiencing clinical deterioration were also assessed. Clinical deterioration was defined as: an MG crisis (weakness severe enough to necessitate intubation or to delay extubation following surgery); significant symptomatic worsening (worsening to a score of 3, or a 2-point worsening from baseline, on any of the individual MG-ADL items other than double vision or eyelid droop, which in the investigator’s assessment was associated with significant symptomatic worsening); or use of rescue therapy for health in jeopardy (administration of rescue therapy to a patient whose health, in the opinion of the investigator, would be in jeopardy if rescue therapy were not given).Efficacy data were analyzed as follows: change from RCP baseline at Week 60 was assessed for all endpoints in both study groups (ravulizumab–ravulizumab and placebo–ravulizumab); change from OLE baseline to OLE Week 2 (MG-ADL and QMG scores), OLE Week 4 (MG-QOL15r and Neuro-QoL Fatigue scores), and OLE Week 34 (all endpoints) was assessed for the placebo–ravulizumab group only. The analysis from the RCP baseline allowed assessment of endpoints throughout the entire study, while the analysis from the OLE baseline allowed assessment of the immediate and longer-term impact of switching to ravulizumab in the placebo–ravulizumab group.Changes in corticosteroid use during the OLE were also assessed. The safety and tolerability of ravulizumab were evaluated based on the incidence of adverse events, clinical laboratory and vital sign findings, and electrocardiogram abnormalities throughout the study (RCP and OLE periods). The potential relationship between each adverse event and the study agent was evaluated by the principal investigators, who were trained in causality assessment. Serious adverse events were also reviewed by the sponsor.

PMC10134722

Statistical analysis

REGRESSION, EVENTS, EVENT

Sample-size calculations for the RCP have been described previously [A mixed model for repeated measures (MMRM) was used to analyze changes from baseline, with the assumption that missing data were missing at random. Missing data were not imputed. Data are shown as least-squares (LS) mean change from baseline with 95% confidence intervals (CIs). The estimates for the RCP were based on an MMRM that included treatment group, stratification factor region, baseline score, study visit, and study visit by treatment group interaction. Visits up to Week 26 were included in the model. The OLE estimates were based on an MMRM that included stratification factor region, baseline score, and study visit. A model was fit for the ravulizumab–ravulizumab and placebo–ravulizumab arms of the OLE analysis set separately.The responder analysis calculated the proportion of patients who achieved a clinical response from the RCP baseline in patients who initiated ravulizumab in the RCP and from the OLE baseline in patients who initiated ravulizumab in the OLE.A generalized estimating equation Poisson regression repeated measures model was used to analyze clinical deterioration event rates, with the number of events as the dependent variable, the logarithm of patient-years as the offset variable, and the study phase indicator (pre-study, placebo, or ravulizumab) as the explanatory factor.The present interim analysis was prespecified. Data cut-off was 9 November 2021, including data for up to 60 weeks from the RCP baseline (34 weeks from the OLE baseline when patients receiving placebo during the RCP switched to ravulizumab). All analyses were performed using Statistical Analysis Software Version 9.4 (SAS

PMC10134722

Discussion

anti-AChR, fatigue

EVENT

The interim results of this long-term extension of the CHAMPION MG study demonstrate that the benefits of ravulizumab are sustained through 60 weeks in patients with anti-AChR antibody-positive gMG. In patients who received ravulizumab during the RCP, improvements in activities of daily living, muscle strength, fatigue, and quality of life were seen by Week 1 and sustained through 60 weeks of treatment.There was a rapid and sustained beneficial response to ravulizumab in patients who switched from placebo to ravulizumab in the OLE, consistent with that observed for patients treated with ravulizumab during the RCP [The criteria for response in the CHAMPION MG study were an improvement of ≥ 3 points on the MG-ADL scale or ≥ 5 points in the QMG score; both exceed the minimal clinically important difference generally accepted for these measures (i.e. ≥ 2 points on the MG-ADL scale and ≥ 3 points in the QMG score) [Changes to immunosuppressant use were permitted only during the OLE. During the OLE period assessed in the interim analysis (up to 34 weeks of ravulizumab treatment) several patients were able to decrease or discontinue their corticosteroid use, suggesting that adults with gMG who are treated with ravulizumab may be able to reduce their regular corticosteroid dosage, and hence lessen the adverse-event burden associated with such treatment.During the RCP, the proportion of patients experiencing a clinical deterioration event was approximately halved in the ravulizumab group compared with the placebo group [The results of this interim analysis support the efficacy of the weight-based dosing regimen with an 8-week dosing interval. This regimen is used for other approved indications and has been shown to provide immediate, sustained, and complete C5 inhibition over the whole dosing interval [The safety profile of ravulizumab in the long-term extension period was consistent with that in the 26-week RCP [The findings of the CHAMPION MG study of ravulizumab are consistent with those of the REGAIN study of eculizumab in anti-AChR antibody-positive gMG [Strengths of the CHAMPION MG study have been previously described [In conclusion, the interim analysis demonstrates that patients who initiated ravulizumab at RCP baseline sustained their improvements for up to 60 weeks, while patients who switched from placebo to ravulizumab at OLE baseline achieved a rapid and sustained improvement in their MG symptoms, consistent with that observed in patients who initiated ravulizumab treatment at the start of the study. The study also demonstrates that ravulizumab has the potential to decrease the rate of clinical deteriorations. The safety profile was consistent with the known safety profile of ravulizumab and no new safety signals were identified. Overall, these findings support the sustained clinical effectiveness and long-term safety of ravulizumab, administered every 8 weeks, in adults with anti-AChR antibody-positive gMG.

PMC10134722

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 236 KB)

PMC10134722

Acknowledgements

RARE DISEASE

We thank the patients who took part in the study and their families, as well as the CHAMPION MG principal investigators, sub-investigators, and study coordinators. We also thank Sivani Paskaradevan (Alexion, AstraZeneca Rare Disease) for critical review of the manuscript; Kathleen Beasley (Alexion, AstraZeneca Rare Disease) for contributions to trial execution and data interpretation; Alice Zangrandi (Alexion, AstraZeneca Rare Disease) for clinical trial oversight; Ahmed Enayetallah, Sam Gokhale, Fanny O’Brien, Rodrigo Pavani, Nishi Rampal (all formerly of Alexion, AstraZeneca Rare Disease), and Nader Najafian (Alexion, AstraZeneca Rare Disease) for their contributions to the trial design, trial execution, and/or data interpretation. Medical writing support was provided by Mary Greenacre and Julie Ponting of Piper Medical Communications, funded by Alexion, AstraZeneca Rare Disease. A list of CHAMPION MG Study Group members is provided in the Supplementary Information.

PMC10134722

Authors’ contribution

RA

AM, DA, TV, RM, MK, JFH Jr contributed to study data acquisition. GF and LG contributed to study design and/or execution. RA provided statistical analyses. All authors contributed to data interpretation and to the critical revision of the manuscript.

PMC10134722

Funding

RARE DISEASE

Open Access funding enabled and organized by Projekt DEAL. This study and all costs associated with development of this publication were funded by Alexion, AstraZeneca Rare Disease.

PMC10134722

Data availability

RARE DISEASE

Alexion, AstraZeneca Rare Disease will consider requests for disclosure of clinical study participant-level data provided that participant privacy is assured through methods like data de-identification, pseudonymization, or anonymization (as required by applicable law), and if such disclosure was included in the relevant study informed consent form or similar documentation. Qualified academic investigators may request participant-level clinical data and supporting documents (statistical analysis plan and protocol) pertaining to Alexion-sponsored studies. Further details regarding data availability and instructions for requesting information are available in the Alexion Clinical Trials Disclosure and Transparency Policy at

PMC10134722

Declarations

PMC10134722

Conflict of interest

Stroke, Muscular Dystrophy, Arthritis, Musculoskeletal, Myasthenia Gravis, Neurological Disorders

RARE DISEASE, MUSCULAR DYSTROPHY, STROKE, ARTHRITIS, SKIN DISEASES, MYASTHENIA GRAVIS, DISEASE, NEUROLOGICAL DISORDERS

Andreas Meisel has received speaker honoraria, consulting fees, or financial research support (paid to institution) from Alexion, AstraZeneca Rare Disease, Argenx, Axunio, Grifols, Hormosan, Janssen, Merck, Octapharma, and UCB. He serves as chairman of the medical advisory board of the German Myasthenia Gravis Society. Djillali Annane has received consultancy fees from Alexion, AstraZeneca Rare Disease. Tuan Vu is the USF Site Principal Investigator for MG clinical trials sponsored by Alexion, AstraZeneca Rare Disease, argenx, Ra/UCB Pharma, Horizon/Viela Bio, Janssen/Momenta, Sanofi, Regeneron, and Cartesian Therapeutics; he receives speaker and/or consultant honoraria from Alexion, AstraZeneca Rare Disease, UCB, and argenx. Renato Mantegazza serves on advisory boards for Alexion, AstraZeneca Rare Disease, UCB, argenx, Catalyst, and Sanofi. He has received speaker’s honoraria from Alexion, AstraZeneca Rare Disease, UCB, and argenx, and consultancy fees from Catalyst. Masahisa Katsuno has received speaker honoraria from Biogen Japan, Chugai, and Eisai, and financial research support from Alexion, AstraZeneca Rare Disease, argenx, Eisai, and Mitsubishi-Tanabe. Rasha Aguzzi and Glen Frick are employees of and own stock in Alexion, AstraZeneca Rare Disease. Laura Gault was an employee of Alexion, AstraZeneca Rare Disease at the time the study and analysis were conducted. James F Howard Jr has received research support (paid to institution) from Alexion, AstraZeneca Rare Disease, argenx, Cartesian Therapeutics, the Centers for Disease Control and Prevention (Atlanta, GA, USA), the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the National Institutes of Health (including the National Institute of Neurological Disorders and Stroke, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), PCORI, Ra Pharmaceuticals (now UCB Pharma), and Takeda Pharmaceuticals; honoraria from Alexion, AstraZeneca Rare Disease, argenx, Immunovant Inc., Ra Pharmaceuticals (now UCB Pharma), Regeneron Pharmaceuticals, Sanofi US, and Viela Bio Inc. (now Horizon Therapeutics); and non-financial support from Alexion, AstraZeneca Rare Disease, argenx, Ra Pharmaceuticals (now UCB Pharma), and Toleranzia AB.

PMC10134722

Ethics approval

The trial protocol was approved by the independent ethics committee or institutional review board at each participating institution. The trial was conducted in accordance with the provisions of the World Medical Association Declaration of Helsinki, the International Conference on Harmonisation E6 Guidelines for Good Clinical Practice, and all applicable regulatory requirements.

PMC10134722

Consent to participate

Informed consent was obtained from all individual participants included in the study.

PMC10134722

References

PMC10134722

Background

endoloops

Polymeric clips are easy to apply, but whether they present more advantages than endoloops is unclear. This single-center, open-label, randomized controlled trial study was conducted to compare the advantages of using a polymeric clip versus an endoloop in terms of the surgical time.

PMC10311724

Methods

perforation, acute appendicitis

SECONDARY, COMPLICATIONS, ACUTE APPENDICITIS

Adult patients who were diagnosed with acute appendicitis without perforation on preoperative abdominal computed tomography and underwent laparoscopic appendectomy between August 6, 2019, and December 26, 2022, were included. Single-blinded randomization was performed in a 1:1 ratio between the endoloop and polymeric clip groups. The primary endpoint was the difference in surgery time between the polymeric clip and endoloop groups. The secondary endpoints were the difference in the application time of each instrument, difference in operation and anesthesia fees, as well as the frequency of complications.

PMC10311724

Results

The completed trial included 104 and 103 patients in the polymeric clip and endoloop groups, respectively. The median surgery time with a polymeric clip was shorter than that with an endoloop; however, the difference was not significant (18 min 56 s vs 19 min 49 s,

PMC10311724

Keywords

PMC10311724

Background

COMPLICATED APPENDICITIS

When performing a laparoscopic appendectomy, an endoloop, an endostapler, or a polymeric clip can be used to ligate and resect the appendiceal stump [During the process of ligating the appendiceal base, an endoloop is relatively difficult to handle, whereas a polymeric clip has the advantage of being easy to apply [Therefore, we conducted an RCT study to compare the operative times of laparoscopic appendectomy for uncomplicated appendicitis using polymeric clips to those using endoloops.

PMC10311724

Methods

This was a single-center, open-label, RCT. This study was approved by the Institutional Review Board (IRB) of the Catholic University of Korea and performed in accordance with the guidelines and regulations of the IRB. Informed consent was obtained from all the included patients. The study was conducted after registration with Korea Clinical Research Information Service (KCT0004154).

PMC10311724

Patients

periappendiceal abscess, perforation, acute appendicitis

INFLAMMATION, APPENDICITIS, ACUTE APPENDICITIS

Nonpregnant adult patients aged 19–70 years who were diagnosed with acute appendicitis without perforation on preoperative abdominal computed tomography (CT) were eligible. Consecutive patients who underwent surgery between August 6, 2019, and December 26, 2022, in Uijeongbu St. Mary’s Hospital were included, and the follow-up date of the last patient was January 04, 2023. The exclusion criteria were as follows: (1) history of abdominal surgery; (2) open conversion; (3) surgery other than laparoscopic appendectomy; (4) suspicion of perforation or periappendiceal abscess in the surgical field; (5) difficulty in applying a polymeric clip owing to a thick appendiceal base or severe inflammation; and (6) the final biopsy result not being appendicitis.

PMC10311724

Sample size calculation

The sample size calculation was based on the results of a previous study that compared the use of polymeric clips with that of endoloops [

PMC10311724

Randomization and blinding

Using SAS ver 9.4 (SAS Institute Inc., NC, Cary, USA) for Microsoft Windows, random assignment numbers were generated, and a random assignment envelope was created. Before a polymeric clip or an endoloop was applied, the envelope was opened, and the patients were assigned to either the intervention (polymeric clip) or the control (endoloop) group. This was a single-blinded study where the use of polymeric clips or endoloops was not blinded to the investigators, including outcome accessors, but to the patients.

PMC10311724

Primary and secondary endpoints

SECONDARY, COMPLICATIONS

The primary endpoint was the difference in surgical time between the polymeric clip and endoloop groups. The secondary endpoints were differences in the time from the introduction of each instrument to appendiceal base cutting, operation and anesthesia fees, as well as the frequency of complications.

PMC10311724

Procedure

COMPLICATIONS, POSTOPERATIVE COMPLICATIONS

The amount of time from the initiation of skin incision to the completion of skin suturing was defined as the total surgical time. To minimize bias in surgical timepoints, the surgical time was subdivided into skin incision, mesoappendiceal dissection (from start to completion time), polymeric clip or endoloop application (from start to appendix cutting time), and skin suture completion time.In both groups, surgery was performed through three abdominal incisions (one with a 12-mm trocar and two with 5-mm trocars) and using a 5-mm scope. The mesoappendix was dissected using an energy and/or monopolar device. When ligating the appendiceal base, two polymeric clips (Gems-clip Plus, size: XL [12 mm]) and one endoloop (Gemsloop-PGLA) were used in the intervention and control groups, respectively. After the appendix was cut, a drainage tube was placed according to the surgeon's judgment. The specimen was extracted using a plastic bag via the 12-mm trocar site and the trocar was then removed, followed by suturing the skin. The operation and anesthesia fees for each surgery were then calculated.Postoperative acute complications were monitored during hospitalization. If the patients agreed and there were no specific complications, they were discharged on the second postoperative day.One to two weeks after surgery, the patients were checked for postoperative complications during an outpatient visit.

PMC10311724

Statistical analysis

Continuous variables are presented as mean and standard deviation in cases of normal distribution, as well as median and interquartile range (IQR) values in cases of non-normal distribution. Categorical variables are presented as frequencies and percentages. To evaluate the difference between the two groups in continuous variables, the normality test was performed followed by the independent T-test or Wilcoxon's rank sum test. For categorical data, a chi-square test or Fisher's exact test was performed. All statistical analyses were performed using SPSS version 21.0 for Windows (IBM Corp, Armonk, NY, USA), and the significance level was set to 0.05.

PMC10311724

Discussion

intra-abdominal, inflammation, 33,260

INFLAMMATION, COMPLICATED APPENDICITIS, COMPLICATIONS, POSTOPERATIVE COMPLICATIONS

In this study, we were unable to verify the superiority of the polymeric clip over the endoloop in laparoscopic appendectomy for uncomplicated appendicitis in terms of shortening the operative time. However, it was confirmed that the application time of the polymeric clip was shorter than that of the endoloop, and no difference in postoperative complications was observed.Several studies have compared the use of polymeric clips, endoloops, and endostaplers for appendiceal base ligation [The advantage of using polymeric clips is that they can be applied precisely to the desired area. The endoloop needs to be tightened for ligation, with the disadvantage that the surrounding tissue may be pinched during the tightening process. In our study, the pre-knotted area was tightened in two cases, and the surrounding tissues (sigmoid mesocolon and terminal ileal tissue) were pinched together. Although it did not cause complications, it made intra-abdominal handling challenging, with disadvantages for accurate targeting.One of the reasons for the failure to prove the superiority of the polymeric clip in reducing surgical time is that the overall time of laparoscopic appendectomy in our study was shorter than that in the study used as a reference for sample size calculation [The major limitation of the polymeric clip is that it can be difficult to apply to a thick appendiceal base or an appendiceal base with severe and friable inflammation [A limitation of our study is that it was not double-blinded because the researcher included in the clinical trial performed the surgery. However, we attempted to avoid bias as much as possible by having a person unrelated to the study check the time difference and divide the time required for surgery for each procedure. Second, the study lacked empirical evidence to quantify the extent of inflammation at the appendiceal base, making it challenging to determine when applying a polymeric clip would pose difficulty. Future studies should focus on preoperative CT findings of inflammation in the appendiceal base, for which polymeric clips are difficult to apply. Third, although there was no statistical difference in surgical fee, the actual price of two pieces of the polymeric clips is cheaper (Gems-clip Plus, ₩7,100 each) than that of one endoloop (Gemsloop-PGLA, ₩33,260). However, there are usually six pieces of polymeric clips (GEMS clips) in a bundle. Therefore, the price for one operation is ₩42,600. We certainly have to purchase a reusable clip applier (₩243,000), but if there is a smaller bundle of fewer than six pieces, the price competitiveness can be better.

PMC10311724

Conclusion

INFLAMMATION, COMPLICATED APPENDICITIS

The use of a polymeric clip is easier and more comfortable than the use of an endoloop in patients with uncomplicated appendicitis in the absence of appendiceal base inflammation. Even if the application of the polymeric clip fails, it can be compensated for using an endoloop or endostapler. Therefore, we suggest considering using the polymeric clip first if the base thickness on preoperative CT is less than 12 mm.

PMC10311724

Acknowledgements

We express our gratitude to GEMSKOREA for providing no-fault compensation for the clinical trials and volunteer insurance.

PMC10311724

Author contributions

KYL and JIL designed the study. KYL collected the data. KYL, YYP, and JIL performed the statistical analysis. KYL, YYP, JIL, and STO interpreted the results of the analysis and prepared the manuscript. All authors contributed extensively to the work presented.

PMC10311724

Funding

No funding was received for this study.

PMC10311724

Declarations

PMC10311724

Competing interests

The authors declare no competing interests.

PMC10311724

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (IRB) of the Catholic University of Korea and performed in accordance with the guidelines and regulations of the IRB. Informed consent was obtained from all the included patients.

PMC10311724

Consent for publication

Not applicable.

PMC10311724

References

PMC10311724

ABSTRACT

coronavirus disease 2019

CHRONIC PANCREATITIS, CORONAVIRUS DISEASE 2019

The authors declare no conflict of interest.Although several antiviral agents have become available for coronavirus disease 2019 (COVID-19) treatment, oral drugs are still limited. Camostat mesylate, an orally bioavailable serine protease inhibitor, has been used to treat chronic pancreatitis in South Korea, and it has an

PMC9872678

KEYWORDS

PMC9872678

INTRODUCTION

deaths, coronavirus disease 2019

CORONAVIRUS DISEASE 2019

Since its emergence in December 2019, coronavirus disease 2019 (COVID-19) has spread worldwide. As of 9 February 2022, the cumulative number of COVID-19 cases was over 399 million, including more than 5.8 million deaths (Camostat mesylate (DWJ1248, Foistar) is an orally bioavailable synthetic serine protease inhibitor and a strong inhibitor of trypsin, plasmin, plasma kallikrein, and thrombin (According to the literature, an Camostat mesylate is a promising candidate for the treatment of COVID-19, as it is orally bioavailable, affordable, and widely available. To explore the possibility of clinical benefit of camostat mesylate in the treatment of COVID-19, we conducted a randomized, placebo-controlled, phase 2 clinical trial in adult patients with mild to moderate COVID-19 (ClinicalTrials.gov registration no. NCT04521296).

PMC9872678

RESULTS

obesity, sore throat, cardiovascular disease, TEAEs, cough, migraine, diabetes

OBESITY, SORE THROAT, VIRUS, CARDIOVASCULAR DISEASE, ADVERSE EVENTS, ADVERSE DRUG REACTIONS, EVENT, CHRONIC RESPIRATORY DISEASE, MAY, PLAQUE, REGRESSION, HIGH BLOOD PRESSURE, MIGRAINE, DIABETES

A total of 365 patients from 21 institutions in South Korea were assessed between February and May 2021, and 342 patients were enrolled in the study (Enrollment and randomization.Of the 342 randomized patients, a total of 323 patients (161 in the camostat group and 162 in the placebo group), excluding 15 who did not receive investigational products and 4 who missed the “Efficacy Variables Check,” were included in the full analysis set (FAS). A total number of 245 patients (116 in the camostat group and 129 in the placebo group), excluding 78 patients from the FAS (6 due to “Inclusion Criteria Deviation,” 1 due to “Exclusion Criteria Deviation,” and 71 due to “IP Handling and Administration”), was included in the modified full analysis set (mFAS). The median age was 53.0 years in the camostat group and 53.5 years in the placebo group, and 53.22% (182/342) were male. In all, 54.39% (186/342) had one or more risk factors, such as cardiovascular disease, chronic respiratory disease, high blood pressure, diabetes, obesity, and smoking, of which 55.81% (96/172) were in the camostat group and 52.94% (90/170) in the placebo group. At baseline, 72.22% (247/342) had a mild and 27.78% (95/342) had a moderate severity of COVID-19 (Demographics and baseline characteristics of the randomized setMin, minimum; max, maximum; BMI, body mass index; NEWS, national early warning score.See the description of the randomized set in Results. For the data below, unless otherwise indicated, the denominator of the percentage is the number of subjects in each group.Testing for difference between DWJ1248 and placebo using two-sample Testing for difference between DWJ1248 and placebo using chi-square test (c) or Fisher’s exact test (f).The denominator of the percentage for individual risk factors is the number of subjects with the risk factor in each group.The denominator of the percentage for COVID-19 antibody is the number of subjects who had a positive result for COVID-19 antibody in each group.The primary endpoint, time to clinical improvement of subject symptoms within 14 days, was not significantly different between the two groups, being 7 days in the camostat group and 8 days in the placebo group (95% confidence interval [CI], 0.84 to 1.43; Kaplan-Meier plot for time to clinical improvement of subjective symptoms.Clinical improvement in subjective symptoms in the FASFAS, full analysis set. See the description of the FAS in Results.Min, minimum; max, maximum; CI, confidence interval.The denominator of the percentage is the number of subjects who have symptoms at baseline for each group.Duration (days) = (date of event/censored, whichever occurs first − date of first IP administration +1); status = event (clinical improvement) if there is clinical improvement at least once by day 14, and status = censored (no clinical improvement) if there is no improvement by day 14 but clinical improvement after day 14 or no improvement by the end of the study or there is rescue therapy usage before clinical improvement by day 14.Testing for difference between DWJ1248 and placebo using the log rank test.Testing for difference between DWJ1248 and placebo using the Cox proportional hazards model with treatment group as a factor and age and risk factor as covariates. If the result or CI was estimated to be infinity, hazard ratio was estimated using Firth’s penalized maximum likelihood and its CI was presented as the profile penalized likelihood confidence interval.The median time to clinical improvement and its 95% confidence interval by treatment group using the Kaplan-Meier curve.In the FAS of the high-risk group, the proportions with improvement of subjective symptoms by day 7 were 45.87% (50/109) and 38.46% (40/104) in the camostat group and the placebo group, respectively (95% CI, 0.77 to 2.31; Clinical improvement of subjective symptoms in high-risk group in the FAS and the mFASFAS, full analysis set; mFAS, modified full analysis set. See the descriptions of the FAS and the mFAS in Results.The denominator of the percentage is the number of subjects in each group.Testing for difference between treatment groups using the chi-square test.Odds ratio was estimated using Firth’s penalized maximum likelihood, and its CI was presented as the profile penalized likelihood confidence interval.Testing for difference between treatment groups using the logistic regression model with treatment group as a factor and age and risk factor as a covariate.In the high-risk group, the ordinal scale score improved by day 7 in 20.00% (18/90) of the camostat group in the FAS, compared to 13.33% (12/90) of the placebo group (95% CI, 0.75 to 3.78; Improvement in ordinal scale in high-risk group in the FAS and the mFASFAS, full analysis set; mFAS, modified full analysis set. See the descriptions of the FAS and the mFAS in Results.The denominator of the percentage is the number of subjects in each group.Testing for difference between treatment groups using the chi-square test.Odds ratio was estimated using Firth’s penalized maximum likelihood, and its confidence interval (CI) is presented as the profile penalized likelihood confidence interval.Testing for difference between treatment groups using the logistic regression model with treatment group as a factor and age and risk factor as a covariate.Virus culture was previously planned as an exploratory endpoint in this study’s protocol. The virus culture test was performed on swab samples obtained from the nasopharynx. For the quantification of SARS-CoV-2, nasopharyngeal swab samples were taken at predetermined intervals. All the clinical samples were transferred to a single central laboratory and were analyzed there. SARS-CoV-2 culture was performed and viral titers were assessed as described previously (Virus culture using plaque assay in SARS-CoV-2-infected patient samples. Error bars show standard deviations.Concomitant medications (Piroxicam patch and Diphenhydramine Hydrochloride patch) used included analgesics, antibiotics, antihistamine, nonsteroidal anti-inflammatory drugs (NSAIDs), cough medicine, sore throat medicine, muscle relaxant, patch, migraine reliever, and analgesic or cough medicine. The proportions of patients receiving the concomitant medications were not significantly different in the two groups, supporting the conclusion that taking camostat mesylate contributed to the improvement in patients’ clinical symptoms, rather than taking other standard-of-care medications (Table S2). Although not statistically different, 60.47% (104/172) of the camostat group and 68.82% (117/170) of the placebo group received cough medicine (95% CI, 59.55 to 69.69; The rates of incidence of treatment emergent adverse events (TEAEs) and adverse drug reactions (ADRs) were not statistically different between the camostat and placebo groups (Incidence of TEAEs and ADRs (safety set)The denominator of the percentage is the number of subjects in each group.Testing for difference between treatment groups using the chi-square test.

PMC9872678

DISCUSSION

ADVERSE REACTIONS, DISEASE PROGRESSION, POSITIVE, ADVERSE EVENTS, CHRONIC PANCREATITIS, SECONDARY, ADVERSE DRUG REACTIONS

In this phase 2 clinical trial, we assessed the clinical benefit and safety of camostat mesylate in the treatment of mild to moderate COVID-19. No primary or secondary endpoint was statistically significant, according to the A recent randomized, placebo-controlled clinical trial showed that camostat mesylate was not effective in clinical improvement, disease progression, or reduction of mortality. The median times to clinical improvement were 5 days in the camostat group and 5 days in the placebo group. The hazard ratio (HR) for 30-day mortality in the camostat group versus the placebo group was 0.82 (CI, 0.24 to 2.79). The median change in viral loads from baseline to day 5 in the camostat group was −0.22 logThe RES Q-HR [Reconvalescent Plasma/Camostat Mesylate Early in SARS-CoV-2 Q-PCR (COVID-19) Positive High-risk Individuals] trial also aims to assess the effectiveness of camostat in prevention of disease progression in high-risk patients. It has recruited 22 patients, and its results are pending (The COMOVID trial, another clinical trial for camostat mesylate in ambulatory adult patients, was terminated due to SARS-CoV2 pandemic evolution, with a decrease in inclusions and widespread distribution of vaccines (Anticough medications were given to 134 patients: 60 patients in the camostat group and 74 patients in the placebo group (In this study, the efficacy of camostat mesylate was evaluated after administrating for 14 days and the safety profiles were monitored up to 28 days according to the requirement of the South Korea Ministry of Food and Drug Safety. The safety profile of patients who received camostat mesylate was similar to that of placebo-treated patients. In addition, the safety of camostat mesylate has been well established. Foistar has been on the market in South Korea and Japan for more than 2 decades as a treatment for chronic pancreatitis. In South Korea, over 22,400,000 tablets have been used from 2012 to 2020, but only 40 adverse events, 11 adverse drug reactions, and 5 serious adverse reactions have been reported (Korea Institute of Drug Safety & Risk Management, unpublished data). These data underscore the potential value of developing camostat mesylate as a safe, orally bioavailable, affordable, and widely available therapeutic agent for COVID-19.Limitations of our study include insufficient power to detect anticipated differences in the primary endpoint; as this was a phase 2 clinical study, the number of participants was small. Our study results did not elucidate clinical improvement with camostat mesylate in mild and moderate COVID-19 patients. However, subgroup analysis of the high-risk group suggested clinical benefit. To further assess clinical efficacy of camostat mesylate, phase 3 clinical studies are needed.

PMC9872678

MATERIALS AND METHODS

PMC9872678

Study design.

MAY, INFECTIOUS, CORONAVIRUS

This study was a double-blind, randomized, placebo-controlled, multicenter, phase 2 clinical trial in patients with mild to moderate COVID-19. Enrollment of participants began in February 2021 and ended in May 2021. There were 21 study sites, all in South Korea. This clinical trial was planned and recruited COVID-19 patients in South Korea in accordance with the quarantine guidelines, “Coronavirus Infectious Disease-19 Response Guidelines (10-2 edition)” (The study protocol was approved by the institutional review board at each study site. Written informed consent was obtained from all patients for participation in this study. This trial was registered with ClinicalTrials.gov (registration no. NCT04521296), and the study protocol can be seen in the supplemental material.

PMC9872678

Patients.

pneumonia, (RT-PCR)-confirmed SARS-CoV-2 infection

PNEUMONIA

Participants who gave informed consent were assessed for eligibility. The inclusion criteria were age 19 years or older, real-time reverse transcription-PCR (RT-PCR)-confirmed SARS-CoV-2 infection, mild to moderate COVID-19, and one or more COVID-19 symptoms. Patients with mild COVID-19 had symptoms of COVID-19 but did not have signs of pneumonia on chest radiography; moderate COVID-19 was defined as subjects with pneumonia but without evidence of severe pneumonia; and severe pneumonia was defined as presenting oxygen saturation (SpO

PMC9872678

Outcome measures.

obesity, cardiovascular disease, diabetes

OBESITY, VIRUS, CARDIOVASCULAR DISEASE, DISEASE, CHRONIC RESPIRATORY DISEASE, SECONDARY, REGRESSION, HIGH BLOOD PRESSURE, DIABETES

The primary endpoint was time (days) to clinical improvement of subjective symptoms within 14 days. A four-point scale (0, none; 1, mild; 2, moderate; and 3, severe) was utilized for subjective symptom assessment (The secondary endpoints were time (days) to clinical improvement of subjective symptoms within 28 days, change from baseline in subjective symptom score, change from baseline in the ordinal scale, and proportion of clinical improvement in the ordinal scale. An 8-point ordinal scale was used in this study, where score 0 was for an uninfected patient state, 1 or 2 for ambulatory, 3 or 4 for hospitalized with mild disease, 5 to 7 for hospitalized with severe disease, and 8 for dead. An improved ordinal scale score was established when the ordinal scale score improved by 2 or more after the baseline among patients whose baseline ordinal scale score was 2 or higher.Subgroup analysis of the high-risk group was conducted, where the high-risk group included patients who were older than 60 years or had one or more risk factors such as cardiovascular disease, chronic respiratory disease, high blood pressure, diabetes, obesity, and smoking.The result of linear regression of the amount of virus (PFU/mL) was obtained using the lm equation of the R program (version 4.0.5).

PMC9872678

Randomization.

obesity, cardiovascular disease, diabetes

OBESITY, CARDIOVASCULAR DISEASE, CHRONIC RESPIRATORY DISEASE, HYPERTENSION, DIABETES

A stratified block randomization with age (<60 years versus ≥60 years) and the presence of risk factors (any versus none of cardiovascular disease, chronic respiratory disease, hypertension, diabetes, obesity, or smoking) as the stratification factors was used. Subject randomization codes were generated by an independent statistician using Statistical Analysis Software (SAS) version 9.4 (SAS Institute, Inc., Cary, NC, USA), and subjects were assigned to the treatment groups by the investigators via an interactive web-response system.

PMC9872678

Statistical analysis.

REGRESSION, EVENTS, SECONDARY

A total of 189 events across both groups was required, which would provide ≥89% power and a two-sided significance level of 5% if the hazard ratio (HR) comparing the camostat mesylate group to the placebo group was ≥1.6. Assuming a 70% probability of events within 28 days across both groups and a dropout rate of 20%, approximately 338 patients (169 patients per group) were determined for the sample size.Efficacy was evaluated by full analysis set (FAS; based on the intention-to-treat principle) as the primary result and modified full analysis set (mFAS) as the secondary result. The FAS population was subjects who received at least 1 dose of the investigational product after randomization and had at least one assessment result for COVID-19 symptoms. The mFAS population was subjects included in the FAS whose investigational product (IP) compliance was 70% or higher without deviations from the inclusion/exclusion criteria.The time to clinical improvement of subjective symptoms (days) was analyzed using the Kaplan-Meier curve and Cox proportional hazards regression model with a treatment group as the factor and stratification factors (age and presence of risk factors) as covariates. The proportion with improvement of subjective symptoms up to 7 days was analyzed using a logistic regression model with the treatment group as the factor and stratification factors (age and presence of risk factors) as covariates. For a sensitivity analysis, the log rank test or chi-square test was additionally performed.Clinical data were collected and validated using the Rave Electronic Data Capture system (Medidata Institute, NY, USA). All statistical analyses were performed with SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA).Virus culture was previously planned as an exploratory endpoint in this study’s protocol. For the quantification of SARS-CoV-2, nasopharyngeal swab samples were taken at predetermined intervals. All the clinical samples were transferred to a single central laboratory and were analyzed there. SARS-CoV-2 culture was performed and viral titers were assessed as described previously (

PMC9872678

ACKNOWLEDGMENTS

INFECTIOUS DISEASES

We thank the South Korean government, including the Ministry of Food and Drug Safety, Ministry of Health and Welfare, Center for Infectious Diseases Research of KNIH, Ministry of Science and ICT, and Pan-Government Support Committee for COVID-19 Treatment and Vaccine Development for their support to progress the clinical trial well.No conflict of interest was declared by any of the investigators.This work was supported by Daewoong Pharmaceutical Co., Ltd. This research was also supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HQ20C0084). Supplemental material is available online only. Supplemental material. Download

PMC9872678

REFERENCES

PMC9872678

Supplementary Information

The use of virtual reality for simulations plays an important role in the initial training for robotic surgery. This randomized controlled trial aimed to investigate the impact of educational video on the performance of robotic simulation. Participants were randomized into the intervention (video) group that received an educational video and robotic simulation training or the control group that received only simulation training. The The online version contains supplementary material available at 10.1007/s11701-023-01556-4.

PMC10374749

Keywords

Open access funding provided by Okayama University.

PMC10374749

Introduction

An increasing number of procedures are being performed as robotic surgery in the fields of gastroenterology, urology, and gynecology [This study aimed to investigate the impact of educational video on performance of robotic simulation training, called the

PMC10374749

Methods

PMC10374749

Trial design

We performed a randomized controlled trial with two parallel training groups; one group received an educational video and robotic simulation training (video group), while the other received simulation training alone (control group). The study protocol was approved by the institutional ethics committee of (No: 2108–017) and was registered at the University Hospital Medical Information Network (No: UMIN000045495). The Consolidated Standards of Reporting Trials (CONSORT) guidelines were followed [

PMC10374749

Participants

MAY

Robotic surgery trainees in our department were recruited between September 2021 and May 2022. The participants included experienced surgeons and surgical trainees who had no experience with robotic simulation training.

PMC10374749

Robotic simulation training

This study was performed using a

PMC10374749

Intervention

Educational videos on the tips and tricks of each drill were created by the principal investigator (KT) (Supplementary Table 1). The participants in both groups received robotic simulation training. However, the video group received an additional educational video training for a few hours prior to starting the robotic simulation. All participants had to perform the nine drills consecutively as one cycle, and complete 10 cycles in total.

PMC10374749

Primary and secondary endpoints

SECONDARY

Assessment outcomes for each drill included overall, efficiency, and penalty scores. Efficiency scores were calculated by evaluating the time to completion, economy of motion, or master workspace range. Penalty scores consisted of excessive force use, instruments out of view, drops, instrument and cone collisions, incorrect rings, missed targets, and misapplied energy time. The overall scores were calculated by subtracting the penalty from the efficiency scores.The primary endpoint was the overall score of all drills in cycles 1–10 in both groups. The secondary endpoint included the overall, efficiency, and penalty scores in each cycle and drill, as well as the learning curves between the groups.

PMC10374749

Sample size and randomization

The sample size was calculated based on the primary end point. Assuming a difference in the mean overall scores between the groups of 15 with a standard deviation of 10 according to our unpublished data, this study required a total sample size of 20 participants (10 participants for each group) to achieve a power of 90% and an alpha error of 5% (two-sided).Randomization was performed by the principal investigator using a random number (Excel RAND) function. The participants were randomly divided into two groups: video and control.

PMC10374749

Statistical analysis

Statistical analysis and sample size calculation were performed using the JMP 11.2.0 software (SAS Institute, Cary, NC, USA). First, the overall, efficiency, and penalty scores of all drills in cycles 1–10 were compared between the video and control groups. Subsequently, the overall, efficiency, and penalty scores in each cycle as well as each drill were analyzed and compared between both groups. Moreover, the detailed penalty scores for each drill were compared between the groups. Finally, a CUSUM analysis was performed to compare the learning curves between the groups. The cumulative sums of the differences in each drill from the total “time to completion” were calculated based on the cycle. A pooled mean CUSUM was plotted to summarize the results [

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Results

PMC10374749

Discussion

This is the first randomized controlled trial to investigate the impact of educational videos on the performance of robotic simulation training. We found that educational video training improved the performance in robotic simulation. Moreover, CUSUM analysis confirmed the positive effect of the educational video on shortening the learning curve.Educational video should be exemplary for early training in robotic surgery and have the potential to maximize trainees’ learning and skill improvement [Regarding the evidence on robotic simulation training, several randomized controlled trials have been performed to investigate the effect of an affordable surgical robot simulator or procedural virtual reality, showing effective impact in improving robotic surgical skills [We determined that the overall scores of all drills, would be the best index for estimating the impact of educational video training. The mean overall scores in the video group were 18.4 times higher than those in the control group, probably due to educational video training.Participants in the control group improved their overall, efficiency and penalty scores through self-learning, and eventually reached the same level as that of the video group. However, the video group had significantly higher efficiency and lower penalty scores, especially during the initial phase. We propose that participants in the video group had improved their scores through both educational video training and self-learning. The penalty scores in the video group were lower throughout the drills, especially in collisions and out-of-view instruments (Fig. CUSUM analysis has been used to evaluate the learning curves for surgical procedures [Considering the positive effect of video training, our findings indicate that surgical video training could lead to improved robotic surgery performance in the clinical setting. Therefore, a structured training model for robotic surgery, that includes simulation, biotissue, and video training, should improve surgical skills and shorten learning curves [The present study had several limitations. Although this was a randomized controlled trial, the sample size was small. Further studies with larger sample sizes are required to externally validate our findings. The association between the performance of simulation training and performance in a real operating room has not yet been investigated. Therefore, future studies focusing on these are required to confirm the effect of simulation training on performance in the clinical setting. Finally, the effect of educational video on each drill was unclear. A further investigation should be helpful to understand which surgical skills can be improved through the video training.In conclusion, this study demonstrated that educational video training can be effective in improving the performance of robotic simulation training and shortening the learning curve.

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Author contributions

K.T. wrote the main manuscript. K.T., N.H., and J.K. prepared figures. All authors contributed to this study, and reviewed the manuscript.

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Funding

Open access funding provided by Okayama University. Financial support was received from Japan Society for the Promotion of Science (grant number 21K16447) and the Okayama Medical Foundation.

PMC10374749

Declarations

PMC10374749

Conflict of interest

Tomokazu

NOMA

Kosei Takagi, Nanako Hata, Jiro Kimura, Satoru Kikuchi, Kazuhiro Noma, Kazuya Yasui, Tomokazu Fuji, Ryuichi Yoshida, Yuzo Umeda, Takahito Yagi, and Toshiyoshi Fujiwara have no conflicts of interest or financial ties to disclose.

PMC10374749

References

PMC10374749

Purpose

OHCA, cardiac arrest, comatose

CARDIAC ARREST, COMATOSE

This study aimed to assess the effect of different blood pressure levels on global cerebral metabolism in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA).

PMC9951410