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AUTHOR CONTRIBUTIONS
M.R.G., S.L.L., W.B.F, M.A.W., and D.L.K. conceptualized and designed the experiments. M.R.G., M.R.A., K.E.K., and A.J.L. performed the experiments. M.R.G and S.L.L. analyzed and interpreted the data. M.R.G. drafted the original manuscript. M.R.G., S.L.L., and A.J.L. contributed to the statistical analysis. All authors...
PMC10727961
FUNDING INFORMATION
This research was supported, in part, by a National Institutes of Health (NIH) grant HL145055 and P20 GM113125.
PMC10727961
ETHICS STATEMENT
Each participant provided written informed consent as approved by the University of Delaware Institutional Review Board.
PMC10727961
Supporting information
Table S1 Click here for additional data file. Table S2 Click here for additional data file.
PMC10727961
ACKNOWLEDGMENTS
We would like to thank our nurse, Wendy Nichols, our undergraduate students, Paige Kutler and Daniel Himsworth, and our study dietitian, Kristina Krieger, for their help during collection and analysis of the data.
PMC10727961
DATA AVAILABILITY STATEMENT
Data are available upon reasonable request to the principal investigator after institutional data transfer agreement approvals.
PMC10727961
REFERENCES
PMC10727961
Background
Recommendations for health care digitization as issued with the Riyadh Declaration led to an uptake in telemedicine to cope with the COVID-19 pandemic. Evaluations based on clinical data are needed to support stakeholders’ decision-making on the long-term implementation of digital health.
PMC10775022
Objective
trauma
This health economic evaluation aims to provide the first German analysis of the suitability of video consultations in the follow-up care of patients in orthopedic and trauma surgery, investigate the financial impact on hospital operations and personnel costs, and provide a basis for decisions on digitizing outpatient ...
PMC10775022
Methods
trauma
We conducted a randomized controlled trial that evaluated video consultations versus face-to-face consultations in the follow-up care of patients in orthopedic and trauma surgery at a German university hospital. We recruited 60 patients who had previously been treated conservatively or surgically for various knee or sh...
PMC10775022
Results
After 4 withdrawals in each arm, data from a total of 52 patients (telemedicine group: n=26; control group: n=26) were used for our analyses. In the telemedicine group, 77% (20/26) of all patients agreed that telemedicine provided for their health care needs, and 69% (18/26) found telemedicine an acceptable way to rece...
PMC10775022
Conclusions
trauma
Our study supports stakeholders’ decision-making on the long-term implementation of digital health by demonstrating that video consultations in the follow-up care of patients in orthopedic and trauma surgery result in cost savings and productivity gains for clinics with no negative impact on patient utility.
PMC10775022
Trial Registration
German Clinical Trials Register DRKS00023445; https://drks.de/search/en/trial/DRKS00023445
PMC10775022
Introduction
trauma
The adoption of digital technologies has progressed only gradually in health care systems, and uncertainty, especially with respect to the suitability and financial effects, has often acted as a drag on the broader use of digital health applications such as telemedicine [To support stakeholders’ decision-making on the ...
PMC10775022
Methods
PMC10775022
Study Design
Trauma, trauma
We conducted an RCT to examine the use of telemedicine in the follow-up care of patients in orthopedic and trauma surgery at the University Hospital of Giessen, Germany, between September 2020 and April 2021. Our study design had 3 main goals: evaluation of patient and physician satisfaction, evaluation of economic and...
PMC10775022
Ethical Considerations
A detailed study protocol for the planned RCT was submitted and approved by the local ethics committee of the University of Giessen before the start of the study (AZ 73/20). Furthermore, the RCT was registered with the German Clinical Trials Register (DRKS00023445). Patients received comprehensive information about the...
PMC10775022
Analysis of Telemedicine Suitability and its Economic Effects
trauma
The consideration of the health provider’s perspective comprised a bilateral analysis. In the first step, it was investigated whether telemedicine is suitable for hospitals in the follow-up care of patients in orthopedic and trauma surgery. As suggested by current literature, the investigation of video consultations’ s...
PMC10775022
Results
PMC10775022
General Findings
knee disorder, shoulder disorder
The health economic evaluation was based on data from 26 patients in the intervention group and 26 patients in the control group after the withdrawal of 4 study participants in both treatment groups. In the telemedicine group, 42% (11/26) of participants were female, and 58% (15/26) were male. In addition, 27% (7/26) o...
PMC10775022
Discussion
PMC10775022
Principal Results
trauma
This health economic analysis from a health provider’s perspective showed important insights for stakeholder decision-making on the long-term use of telemedicine in the follow-up care of patients in orthopedic and trauma surgery by examining both the suitability of video consultations and the associated financial and p...
PMC10775022
Limitations
There are 3 main limitations. On the one hand, the treatment duration was not measured precisely but was collected from the physicians by means of a questionnaire. However, individual deviations should compensate for each other in total. Furthermore, the technical equipment, the internet connection, and the clinical pr...
PMC10775022
Conclusions
trauma
The first health economic evaluation based on data from a German RCT demonstrated that the use of telemedicine might be suitable for the follow-up care of patients in orthopedic and trauma surgery regarding the physician-patient communication and service provided and that video consultations are less time-consuming for...
PMC10775022
Abbreviations
face-to-faceOrganization for Economic Cooperation and Developmentrandomized controlled trialTelemedicine Satisfaction Questionnaire
PMC10775022
Data Availability
The data sets generated and analyzed during this study are available from the corresponding author on reasonable request.
PMC10775022
Background
various B-cell malignancies, RCC, CRC
ADVANCED RENAL CELL CARCINOMA, COLORECTAL ADENOCARCINOMA, CHRONIC GRAFT-VERSUS-HOST DISEASE, RCC
Ibrutinib, a first-in-class inhibitor of Bruton’s tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/ga...
PMC10623721
Methods
RCC
RCC
Ibrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival ...
PMC10623721
Results
RCC
RCC
A total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9–7.5) months in RCC, 4.0 (2.7–4.2) months in GC, and 5.4 (4.1–5.8)...
PMC10623721
Conclusions
SOLID TUMOUR
Clinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours.
PMC10623721
Trial registration
ClinicalTrials.gov, NCT02599324.
PMC10623721
Supplementary Information
The online version contains supplementary material available at 10.1186/s12885-023-11539-1.
PMC10623721
Keywords
PMC10623721
Background
CRC, urothelial carcinoma, UC, various B-cell malignancies, RCC, gastric adenocarcinoma, chronic graft-versus-host disease, RCC
SOLID TUMOUR, UROTHELIAL CARCINOMA, COLORECTAL ADENOCARCINOMA, CHRONIC GRAFT-VERSUS-HOST DISEASE, DISEASES, RCC
Ibrutinib, a first-in-class, once-daily covalent inhibitor of Bruton’s tyrosine kinase (BTK), is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease following the failure of one or more lines of systemic therapy and remains under investigation in these settings and for other ...
PMC10623721
Materials and methods
PMC10623721
Study design and patients
DLTs, hematologic adverse, toxicities, non-hematologic, Tumors, tumour, RCC
DISEASE PROGRESSION, DISEASE, TUMORS, TUMOUR, ONCOLOGY, RCC
This was an open-label phase 1b/2 multicenter study (ClinicalTrials.gov; NCT02599324) conducted between December 2015 and March 2020, to determine the recommended phase 2 dose (RP2D) of ibrutinib combined with everolimus in RCC, docetaxel in GC, and cetuximab in CRC for previously treated patients. The data cutoff date...
PMC10623721
Study treatment
tumour, RCC
TUMOUR, RCC
In phase 1b, the starting dose level for ibrutinib was 560 mg orally once daily. Ibrutinib 560 mg was combined with everolimus 10 mg orally once daily (RCC cohort), docetaxel 60‒75 mg/mFollowing the determination of the RP2D by a Dose Level Review Committee (DLRC), additional patients were enrolled and treated in phase...
PMC10623721
Study objectives
SD, RCC
DISEASE, RCC
The primary objectives of phase 1b were to determine the RP2D for ibrutinib in each cohort: in combination with everolimus in RCC, docetaxel in GC, and cetuximab in CRC. Secondary objectives in phase 1b of each cohort included evaluation of the preliminary safety and tolerability, overall response rate (ORR) per RECIST...
PMC10623721
Assessments and analyses
Tumour
TUMOUR
Tumour response was assessed using computed tomography (CT) or magnetic resonance imaging (in the case of CT contraindication). Imaging was performed at baseline and every 6 weeks thereafter, per the investigator using RECIST v1.1 guidelines, including confirmation of complete and PRs at least 28 days after the criteri...
PMC10623721
Statistical considerations and analysis populations
tumour, RCC
DISEASE, EVENT, TUMOUR, RCC
For phase 1b, data were summarised by dose level for each cohort separately. For Phase 2, efficacy and safety data were summarised by RP2D dose level of ibrutinib for each cohort. The safety population included all patients who received at least one dose of any study drug. The DLT-evaluable population was defined as pa...
PMC10623721
Results
PMC10623721
RCC Cohort
PMC10623721
Phase 1b
RCC
RCC
A total of 10 patients were enrolled in the RCC cohort in phase 1b; patients received everolimus with either 560 mg ibrutinib (
PMC10623721
GC Cohort
PMC10623721
Phase 1b
DLTs, leukopenia
LEUKOPENIA
Twenty-one patients were enrolled in the GC cohort in phase 1b; all patients received 560 mg ibrutinib with docetaxel; median duration of ibrutinib exposure was 2.7 months and median docetaxel exposure was 1.4 months. Fourteen patients were DLT-inevaluable due to dose interruptions. Seven patients were DLT-evaluable. T...
PMC10623721
Phase 1b/2
DISEASE
A total of 46 patients were enrolled in the GC cohort and were treated at the RP2D in phase 1b/2. Twelve patients (26%) had received at least two prior lines of therapy and 15 (33%) had > 2 metastatic sites of disease (Table Among patients who received the RP2D in the efficacy-evaluable population (All 46 patients in t...
PMC10623721
CRC Cohort
PMC10623721
Phase 1b
DLTs
Twenty patients were enrolled in the CRC cohort in phase 1b; 8 and 12 patients, respectively, received 560 mg and 840 mg ibrutinib with cetuximab. Median duration of ibrutinib exposure was 2.7 months and median cetuximab exposure was 2.3 months. Eleven patients were DLT-inevaluable, 10 due to dose interruption because ...
PMC10623721
Phase 1b/2
dermatitis acneiform
DISEASE
A total of 50 patients were enrolled in the CRC cohort in phase 1b/2. All patients had received at least two prior lines of therapy and 27 (54%) had > 2 metastatic sites of disease (Table Among patients who received the RP2D in the efficacy-evaluable population (All 50 patients treated at the RP2D experienced a TEAE of...
PMC10623721
Pharmacokinetics
Ibrutinib was rapidly absorbed with a median time to maximum concentration (t
PMC10623721
Discussion
tumours, gastrointestinal and skin toxicity, tumour, RCC
TUMOURS, TUMOUR, RCC
This multicenter, open-label, phase 1b/2 study of ibrutinib combination therapy in patients with RCC (ibrutinib plus everolimus), GC (ibrutinib plus docetaxel), or CRC (ibrutinib plus cetuximab) demonstrated acceptable safety in patients with advanced tumours. Overall, results presented here suggest that administration...
PMC10623721
Acknowledgements
We thank the patients who participated in the study and their supportive families, as well as the investigators and clinical research staff from the study centers. The authors thank Harisha Atluri, PhD (employed with AbbVie), for assistance with pharmacokinetic data analysis; and Gary Acton, MD (contracted with AbbVie)...
PMC10623721
Authors’ contributions
MWS, FM
D-YO collaborated with the study sponsors to design the study; MAM, DIQ, PJO, IC, SYK, ID, DC, JB, BM, SKW, K-WL, FM, PM, MWS, DW, and HTA collected the study data; EC performed the data analyses; EC, JHR, and JPD confirmed the accuracy of the data and compiled it for analysis; all authors had access to the data and we...
PMC10623721
Funding
This study was sponsored by Pharmacyclics LLC, an AbbVie Company.
PMC10623721
Availability of data and materials
Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at
PMC10623721
Declarations
PMC10623721
Ethics approval and consent to participate
DEL
The protocol was approved by the institutional review boards or independent ethics committees of all participating institutions. The study was approved by the following institutional review boards or independent ethics committees: Asan Medical Center Institutional Review Board 88; CEIm Hospital Universitario Ramon y Ca...
PMC10623721
Consent for publication
Not applicable.
PMC10623721
Competing interests
Pancreatic Cancer, MWS, Novocure
ONCOLOGY, PANCREATIC CANCER, CROSS, EMD
D-YO: consulting/advisory role with AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, Bristol Myers Squibb/Celgene, BeiGene, Basilea, and Turning Point Therapeutics; and research funding from AstraZeneca, Novartis, Array BioPharma, Eli Lilly, Servier, BeiGene, Merck Sharp &...
PMC10623721
References
PMC10623721
Objectives
TG
HIGH TRIGLYCERIDES
Eicosapentaenoic acid in its ethyl ester form is the single active component of icosapent ethyl (IPE). This study was a phase III, multi-center trial assessing the safety and efficiency of IPE for treating very high triglyceride (TG) in a Chinese cohort.
PMC10257163
Methods
TG
Patients having TG levels (5.6–22.6 mmol/L) were enrolled and randomly assigned to receive a treatment of oral intake of 4 g or 2 g/day of IPE, or placebo. Before and after 12 weeks of treatment, TG levels were assessed and the median was calculated to determine the change between the baseline and week 12. In addition ...
PMC10257163
Results
TG
Random assignments were performed on 373 patients (mean age 48.9 years; 75.1% male). IPE (4 g/day) lowered TG levels by an average of 28.4% from baseline and by an average of 19.9% after correction for placebo (95% CI: 29.8%-10.0%,
PMC10257163
Conclusions
high-TG
IPE at 4 g/day dramatically lowered other atherogenic lipids without a noticeable increase in LDL-C, thereby decreasing TG levels in an exceptionally high-TG Chinese population.
PMC10257163
Keywords
PMC10257163
Introduction
death
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, HIGH TRIGLYCERIDES, ASCVD
Atherosclerotic cardiovascular disease, also referred to as ASCVD, was responsible for almost 2.4 million fatalities in China in 2016, making it the primary cause of death globally [Consuming higher amounts of omega-3 fatty acids, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), has been demonstrated ...
PMC10257163
Materials and methods
PMC10257163
Study design and participants
TG
Forty-nine Chinese institutions participated in this phase III clinical investigation. This research was carried out at many sites utilizing a randomized, placebo-controlled, double-blind trial design. The research followed the rules and guidelines set out by local and/or national independent ethics committees, as well...
PMC10257163
Randomization
By using computerized data collection and minimum dynamic randomization, patients were segregated into three groups, with an equal distribution of patients in each group, resulting in a 1:1:1 ratio. According to the baseline plasma TG levels (less than or more than 8.5 mmol/L), gender, and whether or not they had previ...
PMC10257163
Procedures
The framework of the study design was provided (Fig. Study design. Abbreviation: IPE = icosapent ethylFor patients who had not received any other lipid-altering treatment and had been on a stable dosage of statin therapy for more than four weeks (with or without ezetimibe), this screening and stabilization phase lasted...
PMC10257163
Study outcomes
TG
SECONDARY
The median percentage difference in TG levels from the start to the end of the trial, after accounting for the placebo, was the major outcome measure (week 12). The TG baseline was determined using the mean TG value from visit 5 (week 0) as well as the value from the visit before that (one week earlier, visit 4 or visi...
PMC10257163
Safety assessments
treatment-emergent adverse
ADVERSE EVENTS
Evaluations of safety were performed using information gathered from clinical laboratory tests, abdominal ultrasonography, vital signs, electrocardiograms, and physical examinations, as well as from reports of adverse events (AEs). AEs that appeared for the first time or were worse during the double-blind phase were kn...
PMC10257163
Statistical analysis
The primary objective was to determine the placebo-adjusted median percentage difference in fasting TG levels between weeks 0 and 12 of treatment. According to data from the MARINE trial, the difference in effectiveness between IPE 4 g/day and placebo was estimated to be 30% (51% standard deviation). With 100 patients ...
PMC10257163
Results
PMC10257163
Safety
abnormal hepatic function, diarrhea, TEAEs, urticaria, TEAE
PANCREATITIS, URTICARIA
In all therapy groups, the occurrence of TEAE was typically modest and comparable. Most TEAEs were modest and were unrelated to study medications. Drug-related TEAEs with a greater incidence (> 2%) included diarrhea (9.7%, 2.4%, and 5.6% in IPE 2 g/day, 4 g/day and placebo, respectively). Serious TEAEs were recorded wi...
PMC10257163
Discussion
ASCVD, TG, Vascepa
PILES, EVENTS, RECRUITMENT, PATHOGENESIS, ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, ASCVD, ENDOTHELIAL DYSFUNCTION
Triglyceride-rich lipoproteins (TGRLs) are closely associated with the pathogenesis and progression of atherosclerotic cardiovascular disease (ASCVD) via direct arterial wall deposition, endothelial dysfunction, recruitment of monocytes and subsequent foam cell formation, stimulation of inflammatory cytokines, and acti...
PMC10257163
Comparisons with other studies and what does the current work add to the existing knowledge
nonfatal stroke, cardio-cerebrovascular disease, unstable angina, nonfatal myocardial infarction, TG
UNSTABLE ANGINA
According to previously published analyses in a non-Chinese population, the MARINE study demonstrated that 4 g/day IPE reduced within-group TG concentrations by 26.6% in patients with extremely high TG levels (5.6—22.6 mmol/L) without significant increases in LDL-C levels compared to placebo. Our results were consisten...
PMC10257163
Strengths and limitations
EVENTS, HIGH TRIGLYCERIDES
This work included comprehensive analyses of data in Chinese patients, which allowed for a more targeted evaluation of IPE's effectiveness and safety in this population. These data indicated that IPE was effective for the treatment of very high triglyceride condition in Chinese patients, and that it was well-tolerated....
PMC10257163
Acknowledgements
We appreciated the contributions from participants in this study and all the investigators. This study was sponsored by EDDING. Clinical operation, data management and statistical analysis were supported by Tigermed (contract research organization). The manuscript was developed and its content was contributed by all au...
PMC10257163
Authors’ contributions
P.
Z.W., X. Z., Y. Q., S. Z., Y. C., X. C., X. Q., P. L., S. L., S. J., R. M., L. H., L. W., Z. L., Y. S., Z. Q., F. L., C. X. and C. L. collected the data. J. G. design the study and wrote the main manuscript text. All authors reviewed the manuscript. The author(s) read and approved the final manuscript.
PMC10257163
Funding
This study was supported by EDDING.
PMC10257163
Availability of data and materials
The entirety of the data featured in this work is made accessible to interested parties through the author of correspondence.
PMC10257163
Declarations
PMC10257163
Ethics approval and consent to participate
This multi-center, placebo-controlled, randomized, double-blinded, phase III clinical trial was conducted in 39 research centers in China. The research protocol adhered to the International Conference on Harmonization Guidelines for Good Clinical Practice, and regulations and directives set forth by autonomous local an...
PMC10257163
Competing interests
The authors declare no competing interests.
PMC10257163
References
PMC10257163
Background
inadequate HIV testing rate.
Men who have sex with men (MSM) in China hold a low-risk perception of acquiring HIV. This has resulted in an inadequate HIV testing rate.
PMC10504623
Objective
This study aims to investigate whether administering HIV risk self-assessments with tailored feedback on a gay geosocial networking (GSN) app could improve HIV testing rates and reduce sexual risk behaviors in Chinese MSM.
PMC10504623
Methods
SECONDARY
We recruited MSM from Beijing, China, who used the GSN platform Blued in October 2017 in this 12-month double-blinded randomized controlled trial. From October 2017 to September 2018, eligible participants were randomly assigned to use a self-reported HIV risk assessment tool that provided tailored feedback according t...
PMC10504623
Results
In total, 9280 MSM were recruited from baseline and were randomly assigned to group 1 (n=3028), group 2 (n=3065), or controls (n=3187). After follow-up, 1034 (34.1%), 993 (32.4%), and 1103 (34.6%) remained in each group, respectively. Over 12 months, group 1 took 391 tests (mean of 2.51 tests per person), group 2 took ...
PMC10504623
Conclusions
MSM
Repeated HIV risk assessments coupled with tailored feedback through GSN apps improved HIV testing. Such interventions should be considered a simple way of improving HIV testing among MSM in China and increasing awareness of HIV status.
PMC10504623
Trial Registration
ClinicalTrials.gov NCT03320239; https://clinicaltrials.gov/study/NCT03320239
PMC10504623
Introduction
HIV infections, HIV risk perception, MSM
HIV INFECTIONS
Consistent with global trends, China has experienced an increase in HIV prevalence among men who have sex with men (MSM), with the national HIV prevalence estimated to be 5.7% across 2001-2018 [Despite the high burden of HIV infections within MSM communities, HIV testing rates among MSM are low in China, and only half ...
PMC10504623
Methods
PMC10504623
Study Design and Participants
MSM
This double-blinded, triple-arm RCT was conducted among MSM in Beijing, China, between October 2017 and September 2018. Participants were recruited in October 2017 through the popular Chinese gay dating app Blued, which has approximately 480,000 monthly active users in Beijing [
PMC10504623
Randomization and Masking
Participants were simply randomized in a 1:1:1 ratio by a computerized randomization algorithm with SAS 9.3 (SAS Institute, Inc.) into 3 groups (group 1, group 2, and the control group). The assignment of group allocations was masked to both the study staff and participants to ensure double-blinding.
PMC10504623
Procedures
HIV infection, sexual behaviors
HIV INFECTION, RECRUITMENT
Recruitment messages were privately sent through the app to Blued users from a Blued administrative account. The message briefly introduced the study and provided a link to participate. MSM who clicked the link were directed to eligibility screening, the consent form, and the baseline survey. The baseline questionnaire...
PMC10504623
Outcomes
SECONDARY
The primary outcome of interest was the cumulative number of rapid HIV tests taken over 12 months, described as the mean number of HIV tests per person who attended Blued testing sites for testing per year. The secondary outcome was self-reported UAI at each follow-up, which was assessed by asking “In the past three mo...
PMC10504623
Statistical Analysis
REGRESSION
The primary outcome of this study was the mean number of rapid HIV tests per person per year. We estimated a sample size of 1500 participants (500 per group) was needed to detect a difference of 10% or more in the intervention groups, achieving 90% power at a 2-sided significance of 0.05. The sample size calculation as...
PMC10504623
Role of the Funding Source
The study funders had no role in the study design, data collection, data analysis, explanation of results, or manuscript drafting. The corresponding authors had full access to all study data and had final responsibility for the decision to submit it for publication.
PMC10504623