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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 reviewed and approved the manuscript. | 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 care. | 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 shoulder injuries. A digital health app and a browser-based software were used to conduct video consultations. The suitability of telemedicine was assessed using the Telemedicine Satisfaction Questionnaire and the EQ-5D-5L questionnaire. Economic analyses included average time spent by physician per consultation, associated personnel costs and capacities for additional treatable patients, and the break-even point for video consultation software fees. | 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 receive health care services. In addition, no significant difference was found in the change of patient utility between groups after 3 months (mean 0.02, SD 0.06 vs mean 0.07, SD 0.17; | 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 long-term use of telemedicine in orthopedic and trauma surgery, analyses from a health provider’s perspective based on clinical data are required. Critical insights concerning the suitability of video consultations for patient care and the financial effects associated with telemedicine can be obtained by performing health economic evaluations.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, to investigate the associated financial and personnel impact, and to provide a basis for future decision-making on implementing telemedicine from a health provider’s perspective based on data from a randomized controlled trial (RCT). All economic analyses will be conducted from a health provider’s perspective, that is, from the perspective of the economic entity providing the health service. In this analysis, the economic entity providing follow-up care is a German university hospital. University hospitals provide the highest level of care in the German health care system and serve as important pioneers for establishing new standards of care.Germany is the largest European health care market, with health expenditures of €457 billion (US $502.34 billion) in 2021 [Health economic evaluations of medical services and procedures, including telemedicine, are helpful at 2 distinct levels. First, on the macro level, health expenditures constitute a sizable part of spending for national economies. Data from the OECD show that OECD countries’ health care spending averaged about 8.8% of their gross domestic product before the COVID-19 pandemic in 2019. Individual countries, such as the United States at 16.8% and Germany at 11.7%, spent a significantly higher share on health [In this analysis, we go beyond the health economic analysis of the RCT’s implemented scenario of 2 hours of video consultations per week. We extend our analysis with extensive calculations for scaling up video consultations in specific hospital departments as well as the entire hospital, analyzing the health economic effects of video consultations for 1%-10% of all patients who receive outpatient care at the hospital. | 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 environmental impact from a societal perspective, and a health economic analysis of digitization from the hospital’s perspective. The first 2 evaluations have been previously published with a detailed description of our study design [A total of 60 patients previously treated surgically or conservatively in the clinic for various shoulder and knee conditions were recruited for the RCT in the clinic or by telephone and were randomized in a 1:1 ratio. To participate in the study, patients had to be eligible to undergo a video consultation for their follow-up appointment. Patients in the intervention group (n=30) received a 1-time follow-up appointment through an online video consultation with their attending physician. The video consultation could be conducted by patients using a digital health app or a browser-based software. If a video consultation was not possible or if further diagnostics such as imaging were needed, patients could receive a face-to-face (F2F) appointment at any time. Patients in the control group (n=30) attended their follow-up appointment conventionally in the clinic.In the Department of Trauma, Hand, and Reconstructive Surgery at the University Hospital of Giessen, a 1-hour time frame for video consultations was set up 2 days a week during regular clinic consultation hours as part of the RCT. Up to 8 telemedicine appointments were scheduled per week. Patients in both study arms were seen by the same senior physicians. These senior physicians used a laptop equipped with a camera and microphone to conduct the video consultations with a browser-based software. Although the technical equipment was already available in the clinic, additional costs in the form of monthly license fees for the use of the software occurred for the hospital during the study. Due to the simple design of the software, however, no training of the respective physicians and thus no training costs were required. | 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 study before participation and had to provide informed consent. No compensation was provided for participation in the study. | 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’ suitability focused on the effectiveness of physician-patient communication and service provided in the form of a technology evaluation [The descriptive analysis of the questionnaires included the presentation of the mean, SD, median, and relative frequencies. In addition, the Mann-Whitney In a second step, the economic effects of the use of video consultations were evaluated. These economic calculations comprised 4 different aspects with various sensitivity analyses and were guided by recommendations for health economic analyses in the context of eHealth interventions [ | 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) of participants in the telemedicine group were between 18 and 40 years of age, 65% (17/26) were between 41 and 60 years of age, and 8% (2/26) were aged 61 years or older. The reason for a follow-up appointment was a knee disorder in 38% (10/26) of cases and a shoulder disorder in 62% (16/26) of cases in the telemedicine group. In the control group, 38% (10/26) of patients were female, 62% (16/26) were male, 19% (5/26) were between 18 and 40 years of age, 58% (15/26) were between 41 and 60 years of age, and 23% (6/26) were aged 61 years or older. The medical indication of a knee disorder was given to 35% (9/26) of patients in the control group, and 65% (17/26) had a follow-up appointment due to a shoulder disorder. There were no significant differences between patient characteristics in both groups. | 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 personnel effects.The results of the TSQ indicated that the majority of patients positively evaluated the physician-patient communication and service provided through video consultations. These results are similar to findings in other surgical specialties [Although video consultations were 25% (2.69/10.92 minutes) shorter than F2F consultations, there was no significant difference in patient utility regarding health-related quality of life between the telemedicine group and the control group. In a former study, we already compared the EQ-visual analog scale between the intervention and the control group [From the health provider’s perspective, these results suggest that video consultations might be suitable for use in orthopedic and trauma surgery. The potential of video consultations is further underlined by previous studies that found comparable results to F2F consultations in terms of physician and patient satisfaction, efficiency, quality of care, and benefits from a societal perspective [The economic impact of using telemedicine can be differentiated for clinics both as providers of medical services and as employers. As providers of medical services, clinics benefit from productivity gains due to a reduced consultation time, which on the one hand could lead to lower personnel costs and thus relieve the burden on the health care system, and on the other hand could result in an increased capacity of a clinic and thus improve patient care through shorter waiting times and mitigate the shortage of physicians in the health care system [A holistic view of the economic effects of telemedicine, however, must consider not only the cost savings but also the additional costs incurred by the clinic as a result of the technology.A minimum of 23 video consultations per physician per month was required to recoup the costs of investing in telemedicine software through a reduction in personnel costs resulting from time savings. In the sensitivity analysis, the break-even point ranged from 11.54 to 37.92 video consultations. A lower software fee, however, effectively capped the number of video consultations at 20 per month. Whether this is a viable option for decision makers in practice depends on their individual objectives. Competing providers of telemedicine software in Germany may well offer lower fees that would help lower the break-even point. A given hospital’s possibility of negotiating individual terms of use and fee structures with telemedicine providers might be another important aspect to take into account when implementing telemedicine. Finally, physicians’ incomes are rising continuously. The calculations of personnel costs were based on the cost rates in effect at the time the study was conducted. In 2023, salaries will increase by up to 5.13%. The savings of higher personnel costs through telemedicine will then be accompanied by a lower break-even point. The break-even points calculated in earlier contributions by Buvik et al [This health economic evaluation provides clinical evidence on the apparent ability of telemedicine to provide similar patient utility at lower cost and can therefore improve stakeholders’ decisions on implementing telemedicine in the follow-up care of patients in orthopedic and trauma surgery both in and beyond the current COVID-19 pandemic [ | 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 premises were not considered in the overall cost analysis, as these were already available and did not cause any additional costs for the clinic. In the case of a transfer to other clinics, these costs should be examined in advance. Another limitation arises from the response rates to the 2 data collections of the EQ-5D-5L questionnaire: only patients who had completed both questionnaires were included in the calculation to avoid potential bias. As a result, the group sizes considered were limited. | 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 physicians compared with conventional F2F consultations, resulting in personnel cost savings and productivity gains for clinics without any negative impact on patient utility. These findings were collected from the health provider’s perspective and can thus provide targeted support to stakeholders in decision-making on the long-term use of telemedicine. Results might differ for other specialties of surgery and for different implementations of digital health, such as remote monitoring. However, our results could be helpful in estimating the effects before the implementation of digital processes in other specialties.The authors would like to thank Dr med Alexander Eicher for his support in organizing the study.Conflicts of Interest: None declared.Detailed presentation of cost calculations. | 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/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated. | 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 [PFS] for CRC) in phase 2. | 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) months in CRC. | 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 diseases [There remains an unmet need for patients with RCC, gastric adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) who have progressed on previous vascular endothelial growth factor (VEGF)-targeted and mammalian target of rapamycin (mTOR) inhibitors [On this basis, we conducted a phase 1b/2 clinical study to explore the safety, tolerability, and preliminary activity of ibrutinib combination therapy in previously treated patients with advanced solid tumours, including RCC, GC, CRC, and urothelial carcinoma (UC) who had failed multiple lines of therapy. Here we report results from the RCC, GC, and CRC cohorts (UC cohorts to be reported separately). | 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 for this analysis was 19 April 2021.The phase 1b study followed a 3 + 3 + 3 design in each cohort to evaluate dose-limiting toxicities (DLTs) and determine the RP2D. The DLT observation period was 21 days following the initiation of combination therapy at the start of Cycle 1. A DLT was defined as any grade 3 or higher non-hematologic or grade 4 hematologic adverse event (AE) possibly related to either ibrutinib and/or drug combination that occurred during the DLT-observation period. DLTs were assessed in the first three evaluable patients at each dose level by a safety review committee and expanded to 6 or 9 patients if 1 of 3 or 2 of 6 patients experienced a DLT, respectively. The subsequent phase 2 portion of the study utilised a Simon’s 2-stage design in the GC and CRC cohorts. All patients were ≥ 18 years old with adequate hematologic, hepatic, and renal function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (patients with RCC or CRC with an ECOG performance score of 2 were potentially acceptable after a discussion with the medical monitor). Patients had advanced (locally recurrent and/or metastatic) disease with histologically confirmed clear cell RCC, gastric or gastro-esophageal junctional adenocarcinoma or K-Ras and N-Ras wildtype (EGFR-expressing) CRC, with one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Patients were assessed by investigator to be a suitable candidate for the treatment partner (everolimus, docetaxel, or cetuximab) and ibrutinib as per their tumour type. To be eligible for the RCC cohort, patients had received between one and four prior lines of therapy in the advanced setting, including a VEGF-tyrosine kinase inhibitor. For the GC cohort, patients had received between one and three prior lines of therapy in the advanced setting, including a fluoropyrimidine regimen. For the CRC cohort, patients had received at least two and no more than four prior regimens in the advanced setting, which must have included both an irinotecan and oxaliplatin-based regimen unless unable to tolerate irinotecan chemotherapy. Key exclusion criteria included prior anti-cancer therapy within 28 days of the first dose of study drug (including neoadjuvant or adjuvant therapy if disease progression occurred at ≥ 12 months of treatment completion) and prior treatment with everolimus or temsirolimus (RCC cohort), any taxane (GC cohort), or cetuximab or panitumumab (CRC cohort).All patients provided written informed consent for participation in this study as approved by the Institutional Review Board/Research Ethics Board/Independent Ethics Committee before any study-specific screening procedures were performed. | 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 2 at the RP2D to further evaluate the efficacy of the regimen for each specified tumour type as prespecified. | 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 v1.1, disease control rate (DCR; defined as complete response (CR), partial response (PR), or stable disease (SD) ≥ 6 weeks), duration of response (DOR), and pharmacokinetics of the combination regimens.The primary objectives of phase 2 were to assess progression-free survival (PFS) in the RCC cohort and ORR in the GC and CRC cohorts. Secondary objectives in phase 2 included PFS in GC and CRC cohorts, ORR in RCC cohort, and DCR, DOR, overall survival (OS), safety, and tolerability in each cohort. | 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 criteria for response were first met [Plasma samples were collected for all patients for pharmacokinetic (PK) determination of ibrutinib in all cohorts and docetaxel in the GC cohort. | 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 patients from phase 1b who completed ≥ 21 days of treatment or discontinued treatment before 21 days due to a DLT event. Efficacy analyses were performed in the efficacy-evaluable population, defined as eligible patients (including DLT-inevaluable) who received at least one dose of ibrutinib at the RP2D in combination with at least one dose of the companion drug and had at least 1 post-baseline tumour assessment, regardless of treatment duration, or had died prior to the first adequate post-baseline assessment (RCC cohort) or had measurable disease and at least 1 post-baseline tumour assessment (GC and CRC cohorts). When analysing efficacy at the RP2D, the data from patients in phase 1 treated with the RP2D phase 2 were merged prior to analysis.For the RCC cohort, a single interim analysis for PFS futility was conducted when the twenty-fifth patient of 55 total dosed at the RP2D level had completed 6 months of follow-up. The study was designed to detect a 75% increase in median PFS to 8.6 months for ibrutinib plus everolimus with a sample size of 55 efficacy-evaluable patients. Phase 2 of the GC and CRC cohorts followed a Simon’s 2-stage design for patients treated at the RP2D. For the GC cohort, 39 patients were to be enrolled in two stages; if ≥ 2 of 21 patients had a tumour response (PR or CR) in stage 1, whereupon an additional 18 patients were enrolled in stage 2. Treatment was deemed acceptable for further clinical development if ≥ 6 patients responded. The Simon’s 2-stage design provided 80% power to test the historical ORR of 7% against the target ORR of 20%. In the CRC cohort, 40 patients were to be enrolled in two stages; if ≥ 3 of 22 patients were responders in stage 1, then an additional 18 patients were enrolled in stage 2. The Simon’s 2-stage design provided 80% power to test the historical ORR of 10% against the target ORR of 25%. | 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. Two of these seven had DLTs (29%); one patient experienced grade 4 leukopenia for 3 days after receiving ibrutinib 560 mg QD plus docetaxel 75 mg/m | 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 the phase 1b/2 GC cohort treated at the RP2D experienced a TEAE, with grade ≥ 3 TEAEs occurring in 91% ( | 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 of non-DLT AEs and one due to dosing non-compliance. Among the nine DLT-evaluable patients in this cohort, there were no reported DLTs. Therefore, the RP2D used in phase 2 was 840 mg ibrutinib orally daily plus 400 mg/m | 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 any grade, with grade ≥ 3 TEAEs occurring in 68% (The most common TEAEs of any grade included dermatitis acneiform ( | 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 of ibrutinib 840 mg orally with everolimus 10 mg in RCC, ibrutinib 560 mg with docetaxel 60 to 75 mg/mIn metastatic RCC, other combinations, such as sorafenib plus everolimus, have been tested. Nevertheless, excessive gastrointestinal and skin toxicity limited the translation of this combination to the clinical trials. As single agents, everolimus and sorafenib reported PFS of 4.9 and 5.5 months [In both the GC and CRC cohorts, 14 and 11 patients were DLT-inevaluable, suggesting a sick population overall at study entry. Nonetheless, in patients with refractory GC, ibrutinib plus docetaxel was associated with a higher ORR of (18%) relative to single-agent docetaxel (7%) but a similar 6-month PFS (29% and 26%) [The safety profiles for each of the drug combinations were generally consistent with the known safety profiles for the individual agents used in the study, suggesting no significant interaction between ibrutinib and partner agents and were as expected for patients with these advanced tumour types considering prior therapies and treatment duration. TEAEs related to companion drugs in this study were consistent with those reported previously in everolimus in RCC, [The heavily pretreated patient populations in this study may not have been the optimal contexts for evaluation of novel ibrutinib combination regimens, as evidenced by the modest efficacy observed relative to historical controls. However, the generally manageable safety profile seen across all three cohorts and the high levels of relative dose delivery of both ibrutinib and partner agents support the feasibility of the regimens studied, thereby warranting consideration of further evaluation in earlier stage settings and/or with different partner agents. | 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), for critical review of the manuscript. Medical writing support was provided by Cindi A. Hoover, PhD, and funded by Pharmacyclics LLC, an AbbVie Company. | 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 were involved in the interpretation of data, contributed to the manuscript review and revisions, and approved the final version for submission. | 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 Cajal Secretria del Comité; Chesapeake Institutional Review Board; Chonnam National University Hwasun Hospital Institutional Review Board; Dignity Health Bay Area Regional Institutional Review Board; Henry Ford Health System Research Administration; Korea University Guro Hospital Institutional Review Board; London-Surrey Borders Research Ethics Committee; Nebraska Methodist Hospital Institutional Review Board; Norwalk Hospital Institutional Review Board; Penn State Milton S. Hershey Medical Center, Penn State College of Medicine Human Subjects Protection Office; Samsung Medical Center Institutional Review Board 81; Severance Hospital Yonsei University Health System 50–1 Institutional Review Board; Seoul National University Bundang Hospital Institutional Review Board 82; Seoul National University Hospital Institutional Review Board 101; The Catholic University of Korea Seoul St. Mary’s Hospital Institutional Review Board 222; Tufts Medical Center/Tufts University Health Sciences Institutional Review Board; University of Kansas Medical Center Institutional Review Board; University of Pennsylvania Office of Regulatory Affairs; University of Southern California Health Sciences Institutional Review Board; University of Texas Medical Branch Institutional Review Board; Vanderbilt University Institutional Review Board, Wake Forest University Health Sciences Institutional Review Board; and Western Institutional Review Board. All patients were required to confirm their willingness to participate in this study as approved by the institutional review boards or independent ethics committees at each participating study site before any study-specific screening procedures were performed. All patients provided written informed consent for participation in this study as approved by the Institutional Review Board/Research Ethics Board/Independent Ethics Committee before any study-specific screening procedures were performed.Patients were also required to grant permission to use protected health information per the Health Insurance Portability and Accountability Act. In addition, patients were required to consent to and sign all approved amendments per the site institutional review board or independent ethics committee guidelines during the course of the study.The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Guidelines for Good Clinical Practice. | 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 & Dohme, and Handok; MAM: consulting/advisory role with Merck Sharp & Dohme, Bristol Myers Squibb, Eli Lilly, and Servier; and travel accommodations from Eli Lilly; DIQ: honoraria from and consulting/advisory role with Astellas, Bristol Myers Squibb, Bayer, Pfizer, Merck, EMD Serono, Genentech/Roche, and Seagen; and employment with AbbVie; PJO: consulting/advisory role with Genentech and Array BioPharma; research funding from Pfizer, Genentech, Bristol Myers Squibb, AstraZeneca, GlaxoSmithKline, Five Prime Therapeutics, Forty Seven, Merck, Syndax, bbi-biotech GmbH, Novartis, Celgene, Incyte, Eli Lilly/ImClone, Array BioPharma, H3 Biomedicine, Taiho, Minneamrita, Pharmacyclics LLC, an AbbVie Company, and Mirati; and expert testimony for Bayer and Eli Lilly; IC: honoraria from Eli Lilly and Eisai; consulting/advisory role with Eli Lilly, Bristol Myers Squibb, Merck Sharp & Dohme, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, AstraZeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, and Astellas; and institutional research funding from Eli Lilly, Sanofi Oncology, and Cilag-Janssen; SYK: institutional research funding from F. Hoffman-La Roche; ID: honoraria from Roche-Genentech, Merck Sharp & Dohme, Bristol Myers Squibb, Ipsen, AstraZeneca, and Eusa Pharma; consulting/advisory role with Roche-Genentech, Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Ipsen, AstraZeneca, Debiopharm, Seagen, and Pharmacyclics, LLC, an AbbVie Company; institutional research funding from Roche and AstraZeneca; and travel accommodations from Ipsen and AstraZeneca; DC: honoraria from and consulting/advisory role with Astellas, Janssen, Roche, Merck, Ipsen, Exelixis, Pfizer, Bristol Myers Squibb, Eisai, and AstraZeneca; JB: consulting/advisory role with Ipsen, Bayer, QED, Eisai, Seagen, Mirati, Clovis, Insmed, and EMD Serono; institutional research funding from AbbVie, Bristol Myers Squibb, Boston Biomedical, I-Mab, Dragonfly, Symphogen, Immunomedics, Eli Lilly, Bayer (Loxo), EMD Serono, Incyte, Karyopharm, Pfizer, Astellas, and Atreca; travel accommodations from EMD Serono and Seagen; and other relationship (data and safety monitoring board) with Novocure, Karyopharm, and Pancreatic Cancer Action Network; BM: research funding from Roche, Bayer, and Janssen; speakers bureau with Roche, Sanofi, Janssen, Astellas, Pfizer, Novartis, Bristol Myers Squibb, and Ipsen; and travel accommodations and expenses from Pfizer and Janssen; SKW: stock or other ownership in Horizon Therapeutics, Merus, and Iovance Biotherapeutics; and institutional research funding from Daiichi Sankyo, Bayer Health, Acceleron Pharma, Sotio, Rogosin Institute, Pharmacyclics LLC, an AbbVie Company, Merck Serono, EMD Serono, Sanofi, Novartis, Nektar, Seagen, Astellas Pharma, Aleon Pharma, Bristol Myers Squibb, and Regeneron; K-WL: honoraria from Bristol Myers Squibb, Eli Lilly, and Genexine; consulting/advisory role with ISU ABXIS, Bayer, Bristol Myers Squibb, and Daiichi Sankyo; and institutional research funding from Ono Pharmaceutical, Merck Sharp & Dohme, AstraZeneca/MedImmune, Merck KGaA, Pfizer, MacroGenics, Green Cross, ABL Bio, Y-Biologics, Daiichi Sankyo, Taiho Pharmaceutical, Five Prime Therapeutics, Oncologie, Pharmacyclics, LLC, an AbbVie Company, LSK.BioPharma, ALX Oncology, Zymeworks, BeiGene, and Genexine; FM: consulting/advisory role and speakers bureau with, and travel accommodations from Servier; PM: reports no conflict of interest; MWS: research funding from Pharmacyclics LLC, an AbbVie Company; DW: consulting/advisory role with Castle Biosciences; EC: employment with and stock ownership in Pharmacyclics LLC, an AbbVie Company; JHR: employment with AbbVie and stock ownership in AbbVie; immediate family member stock ownership in Celgene/Bristol Myers Squibb; JPD: employment with and stock ownership in Pharmacyclics LLC, an AbbVie Company; HTA: employment with HCA Healthcare UK/Sarah Cannon Research Institute; honoraria from BeiGene, Bicycle, LabGenius, CellCentric, iOnctura, Taiho, Servier, and Guardant; consulting/advisory role with iOnctura, Engitix, LabGenius, CellCentric, Daiichi Sankyo, Bicycle, and BeiGene; institutional research funding from Sarah Cannon Research Institute; and speakers bureau with Servier and Guardant. | 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 to examining TG levels, the impact of such treatments on other lipid changes was also investigated. The official Drug Clinical Trial Information Management Platform has registered this study (CTR20170362). | 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 to decrease the levels of total cholesterol [However, there is a scarcity of multi-center evidence on the consequences of IPE launched in a Chinese population-based cohort study. This study was aimed at assessing the safety and effectiveness of treating Chinese patients who have extremely high triglyceride levels (5.6 to 22.6 mmol/L). | 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 as the principles outlined in the Helsinki Declaration. Institutional review boards authorized the protocol, consent forms, and other pertinent documentation. Before the trial began, all the patients signed informed consent forms. CTR20170362 was the registration number for this study.Eligible participants were men and women over the age of 18 whose TG levels fell between 5.6–22.6 mmol/L (with a stable diet and physical activity). If statin medication (with or without ezetimibe) was used, the dosage must have been stable for at least four weeks before the TG qualifying visit (visit 3 [week 2]).Participants were required to safely stop taking any medications before the screening visit and throughout the course of the study, including niacin doses greater than 200 mg daily, fish oil or other foods rich in omega-3 fatty acids, fibrates, and any herbal or food additives that may regulate lipid levels. | 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 previously taken a statin (yes or no), patients were allocated to one of the groups randomly. | 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 six weeks. For patients who stopped receiving other TG-altering treatments, it persisted for eight weeks (as mentioned above).In order to ensure that the patients adhered to the lifestyle recommendations, visit 2 included a telephone interview. If patients' average overnight TG levels at visits 3 and 4 (separated by one week) were in the range of 5.6–22.6 mmol/L, they were eligible to participate in the following 12-week double-blind session. Patients were offered an optional TG measurement at visit 4.1 and an extra stabilization week if average fasting TG levels dropped outside of this range (one week later). According to the average fasting TG levels at visits 4 and 4.1, eligibility was reevaluated.Those who met the inclusion criteria were monitored for a week before being randomly assigned to receive either 4 g/day of IPE (take two capsules of IPE, each with a dosage of 1 g, twice a day), 2 g/day of IPE (take one capsule of IPE with a dosage of 1 g and one capsule of placebo twice a day), or a placebo capsule (two placebo capsules twice daily) starting at visit 5 (week 0).Mealtime, oral study medications were taken with or at the end of meals. All study medications (both IPE and placebo capsules) were provided by Amarin Pharmaceuticals Ireland Limited, which is based in Dublin, Ireland. Light liquid paraffin was used to fill each placebo capsule. | 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 visit 4.1). The mean values of TG at visits 8 (week 11) and 9 (visit 9) were used to compute the TG levels after the trial (week 12). The secondary objectives comprised median percentage changes in VLDL-C from baseline (visit 5, week 0) to the trial conclusion (visit 9, week 12). These adjustments were made to account for the placebo effects. The exploratory endpoints are low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and very low-density lipoprotein cholesterol (VLDL-TG). | 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 known as treatment-emergent adverse events (TEAE). | 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 in each group, IPE 4 g/day, and placebo, there would be 98.5% statistical test power at a two-sided significance level of 0.05 (based on the PASS 12.0 software). It was anticipated that there was a difference of 25.4% (with a standard deviation of 51%) between IPE 2 g/day and placebo (data from the MARINE study). If 100 patients were assigned to the IPE 2 g/day group, and 100 patients to the placebo group, the statistical test would have a power of 94% at a significance level of 0.05 for two-sided analysis (based on PASS 12.0 software). A total of 360 patients were intended for randomization, with 120 in each group, taking into account a 20% dropout rate from randomization until study completion.The statistical evaluation was produced with SAS 9.4. For the main effectiveness analysis, the modified intent-to-treat (mITT) data set, per protocol set (PPS) data, and Safety Set (SS) data were used. A covariance model (ANCOVA) was used for the effectiveness analysis, with the treatment group, gender, and baseline statin usage as variables and baseline TG value as a covariate. If a normal distribution or homogeneity of variances could not be met, nonparametric intergroup comparisons were made using Wilcoxon rank-sum tests with the interquartile and median ranges for each group. Additionally, Hodges-Lehmann two-sided 95% and 99% CIs for the predicted median and treatment differences for each comparison across groups were supplied. In all two-sided statistical tests, the threshold for statistical significance was established at | 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 with a low incidence (2.4%, 3.2%, 2.4% in IPE 2 g/day, 4 g/day and placebo, respectively). There were no drug-related severe TEAEs. Due to TEAEs, three patients in the IPE 4 g/day group (2.4%; one patient each with abnormal hepatic function, urticaria, and severe pancreatitis) and one patient in the placebo group (0.8%; hypersensitive response) terminated the trial. Only two incidences of drug-related TEAEs resulting in the withdrawal of the research (one each in IPE 4 g/day was urticaria and in the placebo group was a hypersensitive response) was detected. Glucose and HbA1c responses were comparable across the IPE and placebo groups. Vital signs, electrocardiography, liver function tests, and serum creatinine phosphokinase levels were not statically significant after different IPE dosing treatments. | 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 activation of platelets [IPE (Vascepa®) is an omega-3 fatty acid medication possessing a highly refined (96%) EPA ethyl ester that is devoid of DHA [For the main effectiveness objective, IPE at 4 g per day lowered TG levels by 28.4% from baseline and substantially decreased TG levels by 19.9% when adjusted for a placebo. Difference in terms of TG level changes between IPE 2 g/day and placebo didn’t reach the significance level, but there was a numerical decrease in TG levels (median 12.0%) from baseline. At 4 g/day, IPE substantially lowered VLDL-C levels by a median of 27.9% when adjusted for placebo and also decreased other TG-related lipid profiles (non-HDL-C and VLDL-TG). At 2 g per day, IPE also exhibited reducing effects, but this was not statistically significant ones. These findings showed that IPE has a dose-dependent impact, with a maximum benefit of 4 g per day.Moreover, compared to placebo, IPE did not substantially elevate LDL-C levels in this investigation, as is often reported with mixed omega-3 fatty acid agents (including both EPA and DHA) in comparable patient populations [While the magnitude of the median placebo-adjusted TG reduction in the current study appears to be slightly lower than that in the MARINE study (-5.0% and -19.9% at 2 g/day, and -19.9% and -33.1% at 4 g/day, respectively), the within-group percent differences from baseline to 12-week endpoint in each IPE group are very similar to the changes in the MARINE study (12.0% vs 19.9% in 2 g/day, and 28.4% vs 33.1% in 4 g/day, respectively). The following are possible explanations for the apparent disparities between these two investigations. To begin, the baseline TG level differed between the two trials. According to the findings of this research, the TG level at baseline was higher than what was seen in the MARINE study (median 9.37 mmol/L vs 7.67 mmol/L, and the proportion of TG > 8.5 mmol/L is 54.2% vs 39.3%, respectively). The greater the TG level, the more difficult it is to lower it. Second, in this trial, TG fell by a median of 6.2% from baseline in the placebo group, but increased by a median of 9.7% in the MARINE placebo group. This might be attributed to improved nutrition management in the Chinese research population. As a result, in the analysis, the placebo-corrected decrease seemed to have been limited. IPE at 4 g/day demonstrated comparable TG-lowering effects in subgroup analyses with varying baseline TG levels, sex, and statin usage to those of the whole mITT sample. As a result, IPE effects were predictable across patient subgroups.The MARINE study showed that treatment with 4 g or 2 g /day of IPE for 12 weeks statistically significantly increased EPA concentration (in both plasma and red blood cells) in a dose-dependent manner compared to placebo. A linear relationship between EPA levels (in plasma and red blood cells) and TG reduction was observed. Patients in the IPE 4 g/day group had a larger mean percent increase in EPA concentration (in plasma and in red blood cells) and a larger median percent decrease in TG from baseline than patients in the IPE 2 g/day group and the placebo group. Mean levels of plasma and red blood cell fatty acid parameters EPA and DPAn-3 (a metabolite of EPA) also increased in a dose-dependent manner.The results of China phase I study and the population pharmacokinetic (PopPK) analysis of IPE phase I studies in China and the United States showed that within the dose range of 2 g/day to 4 g/day, the baseline-corrected plasma total EPA, red blood cell total EPA and plasma unesterified EPA concentration showed dose proportional property. The dose effect of IPE 2 g/day and 4 g/day was linear. There was no significant difference in the plasma EPA exposure level between Chinese and Americans. It indicates that PD/PK study of IPE has consistency, and the TG lowering effect in different ethnic populations are consistent, and there is no significant racial difference.IPE has been commercially used around the world for many years. Piles of clinical data and experience has been accumulated. Based on the results of phase I studies in China and abroad, it showed the linear correlation between IPE, EPA and TG. The phase III results are consistent with PD/PK studies, which predict that there should be a linear relationship between EPA levels (in plasma and red blood cells) and TG reduction after IPE treatment in the Chinese population. And the main purpose of the phase III study in China is to evaluate the effectiveness and safety of reducing TG after 12 weeks of IPE treatment in the Chinese population. At the same time, TG is a routine clinical detection item in China, and patients generally do not detect EPA in Chinese clinical practice. Therefore, this study set the primary endpoint as TG and did not measure EPA. EPA levels were also examined in the REDUCE-IT study, and higher EPA levels were found to confer cardiovascular benefits. The time of this study was short, and the study endpoints did not involve long-term follow-up and reduction of cardiovascular events, which is one of the reasons why this study did not design to detect EPA.Since this study lacking in the detection of EPA level, larger sample studies will continue to carry out in the Chinese population based on the above research data, and further explore the relationship between EPA levels and TG-lowering efficacy and cardiovascular risk reduction. Unfortunately, this study currently unable to additionally detect the level of EPA because of the original study design and locked database.The acceptability and safety profile results of IPE were consistent with those of prior research [Apart from these, other polyunsaturated fatty acids have also been shown to process lipid-modifying effects, such as linolenic acid and dihomo-γ-linolenic acid (DGLA). It is well established LA consumption leads to lower cholesterol level [ | 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 consistent with the findings of MARINE study [Regarding the clinical advantages on cardio-cerebrovascular disease, it was determined that a daily dosage of 4 g of IPE reduced the risk of nonfatal myocardial infarction, cardiovascular mortality, coronary angioplasty, nonfatal stroke, or unstable angina by 25% [ | 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. Furthermore, the study was able to identify an effective dosage for Chinese individuals, which may be different from the dosage used in other Asian populations. However, this study did not measure EPA levels or its metabolites. This is a limitation of the current work, which requires future work to explore the relationship between EPA levels and TG-lowering efficacy and cardiovascular risk reduction. The time of this study was short, and the study endpoints did not involve long-term follow-up and reduction of cardiovascular events, which is another limitation of this work. In addition, this study did not set up a comparison with other fatty acids, so there is still a lack of difference in the efficacy of EPA in reducing plasma TG level compared with other fatty acids. The cardiovascular benefits of EPA or other fatty acids may need to be further consolidated in a new randomized controlled study. In the future, more evidence is needed to further explore and compare the mechanism and efficacy of various fatty acids. | 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 authors. During the development phase, the manuscript was subjected to a review by the EDDING and Amarin team, who provided suggestions. However, it is noteworthy that the authors retained the sole responsibility for final opinions, content, interpretation, and conclusions pertaining to the study data. The authors acknowledge the EDDING and Amarin team for their valuable input during the manuscript development. | 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 and/or national ethics committees. The Helsinki Declaration was followed in conducting all procedures. Institutional review boards granted approval of the protocol, consent forms, and additional pertinent documentation. Prior to the commencement of the study, signed informed consent were provided by all patients. The registration number was CTR20170362 (available at: | 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 to transmission risk (group 1), access to the same HIV risk assessment without feedback (group 2), or government-recommended HIV education materials (control). All interventions were remotely delivered through the mobile phone–based app Blued, and participants were followed up at 1, 3, 6, and 12 months from baseline. The number of HIV tests over the 12-month study was the primary outcome and was assessed using an intention-to-treat analysis with an incident rate ratio (IRR). Unprotected anal intercourse (UAI) over 6 months was assessed by a modified intention-to-treat analysis and was the secondary outcome. All statistical analyses were conducted in SAS 9.3 (SAS Institute, Inc.), and a | 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 352 tests (mean of 2.01 tests per person), and controls took 295 tests (mean of 1.72 tests per person). Group 1 had significantly more HIV testing than the control group (IRR 1.32, 95% CI 1.09-4.58; | 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 of MSM reported to have ever tested for HIV [To improve HIV risk perception among MSM, HIV risk assessment tools have been developed in many countries to motivate HIV testing and the initiation of pre-exposure prophylaxis (PrEP) [ | 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 covered demographics, HIV testing history, GSN app use, and sexual risk behaviors. Group 1 and group 2 took the HIV RISK Assessment tool at baseline and 6 months after randomization. The HIV RISK Assessment tool was based on a validated, 8-item questionnaire developed in China [Group 1 also received tailored feedback based on their responses to the HIV RISK Assessment tool, which included their HIV risk score, probability of acquiring HIV, high-risk sexual behaviors contributing to their risk of HIV infection, and personalized measures to reduce their risk of HIV infection. An example of this bespoke feedback is captured in All participants, regardless of randomization, received a link at baseline and 6 months post randomization to sign up for free HIV testing at convenient drop-in testing sites managed by Blued. If participants scheduled an HIV test, they would receive an SMS text message confirming the location and time of the appointment. Only rapid screening tests were conducted at Blued drop-in testing sites, and those who tested positive were referred to the appropriate district CDC in Beijing for further HIV confirmatory testing by Western blot test and were engaged in antiretroviral therapy, if appropriate. The number of rapid HIV tests taken by participants was collected by working staff at drop-in testing sites run by Blued 1 year after randomization.Follow-up was conducted at 1 month, 3 months, 6 months, and 12 months following randomization, and the same baseline questionnaire was to be completed, excluding demographic information. The baseline survey was not administered at 12 months post randomization due to low follow-up rates. All questionnaires were conducted on the internet through a unique website developed for the study. If participants did not respond to the initial follow-up surveys, a second link was sent as a reminder 1 week later. Participants were considered lost to follow-up if they had not responded to the second reminder within 1 week.An example of 1 of the 8 items in the HIV RISK Assessment tool. The text reads: “How many HIV-positive homosexual partners did you have in the past 6 months?” Participants would then choose one of the responses: “1,” “2-5,” “6-9,” or “more than or equal to 10”.Tailored prevention messaging based on the participant’s risk assessment score. The text reads: “HIV risk assessment report: your current HIV infection risk score is 6 (the total score is 15), and your probability of HIV infection is 28.09% according to your answers to the HIV risk assessment tool. Measures you should take include ordering an offline HIV test in one of the app-based clinics by clicking the button and reducing the number of homosexual partners.”. | 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 months, how often did you use condoms for anal sex with a man?” with 4 options: never, sometimes, often, and always. The first 3 options were classified as UAI, and the last as non-UAI. The proportion of UAI was calculated as the number of participants who reported UAI in the past 3 months divided by the number of participants who completed at least one follow-up. | 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 assumed that those in the control group receive an average of 1 HIV test per year, based on a previous study on GSN app users in China [The mean number of rapid HIV tests per person per year in each group was calculated and analyzed using zero-inflated Poisson regression analysis, estimating the ratios of HIV testing rates in the 2 intervention groups compared to the control group, and reported as incident rate ratios (IRRs) and 95% CIs. The primary analysis was conducted with the intention-to-treat analysis. The proportion of participants who self-reported UAI at each follow-up (1 month, 3 months, and 6 months after randomization) was compared between the study groups using longitudinal, multilevel logistic regression models to account for repeated measures with each individual. The within-individual variable was time (baseline and follow-ups), and the interindividual variable was the intervention group. Adjusted multilevel logistic regression modeling evaluated differences in UAI among study groups. UAI analyses were done with the modified intention-to-treat analyses, excluding those who were never followed.Descriptive statistics for demographic characteristics, HIV testing history, and sexual risk behaviors were calculated using baseline data and then compared with chi-square tests for categorical variables between those who finished at least one follow-up and those who did not. All statistical analyses were performed with SAS software (version 9.3; SAS Institute, Inc.), and a | 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 |
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