title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
|---|---|---|---|---|
Conclusions | Voluntary APN can be successfully implemented with a prison population and within a prison setting despite the many barriers to HIV notification that incarceration presents. Our findings suggest that the Impart model holds considerable promise to increase partner notification, HIV testing and diagnosis among sex and drug‐injecting partners of HIV‐positive incarcerated men.This study is registered at Clinical trial registration number: NCT04155320 | PMC10281637 | ||
INTRODUCTION | An estimated 3.8% of the world's prison population is HIV positive [With assisted partner notification (APN), health workers are trained to encourage and assist people diagnosed with HIV to inform their at‐risk partners of possible HIV exposure and the need for HIV testing. Research demonstrating APN's effectiveness in successfully promoting HIV disclosure to partners, HIV testing, diagnosis and treatment referral has accumulated for over three decades. Two early U.S. studies showed that APN was feasible in notifying sex and needle‐sharing partners of people diagnosed with HIV [Indonesia's incarcerated population is the eight largest globally, with more than a quarter million inmates [This research helps to affirm and assist the use of APN in prisons and other criminal justice facilities by implementing and comparing the efficacy of the Impart model of APN that we developed for prison populations versus sole reliance on prison inmates to inform their partners themselves (standard of care). With Impart APN, incarcerated people with HIV voluntarily identify and provide names and contact information for partners in the community with whom they may have shared HIV exposure before incarceration. They then select which of these partners to notify themselves or to have informed anonymously by an Impart two‐person team consisting of a nurse and community healthcare worker. Our study examines the outcome of each form of notification on how many at‐risk partners in the community are notified, their gender and type of risk exposure, and HIV testing outcomes. Its findings respond to the need for research on the effectiveness of APN programmes [ | PMC10281637 | ||
METHODS | PMC10281637 | |||
Ethical statement | The Impart model and the procedures for this research were designed or selected in full recognition of the special ethical challenges of protecting the rights and safety of prisoners as a particularly vulnerable research population [ | PMC10281637 | ||
Study design | SECONDARY | Our study population is comprised of HIV‐diagnosed men (index participants) receiving health services through HIV subspecialty clinics located within each jail and prison facility. A two‐group randomized trial was used to evaluate the effects of the prison‐based Impart APN model on partner notification and HIV testing outcomes. Index participants were allocated randomly to either to a self‐tell notification only standard of care condition or to Impart APN choice (active intervention) condition that allowed index participants to choose per partner between self‐tell or having an Impart team (consisting of an HIV‐trained nurse and outreach healthcare provider) notify the partner without revealing the identity of the index participant who named them. Approximately equal numbers of index participants were allocated to the intervention and control conditions per site, using block randomization to ensure balance in the two groups over time.Our primary outcome was partner notification within 6 weeks as reported by the index participant or APN notifier. As secondary outcomes, we compared the number of partners in either group who by the end of this period had completed HIV testing including those who subsequently were HIV diagnosed. With permission from index participants, “self‐tell partners” in both study arms were contacted at the end of 6 weeks to verify if they had been notified and to obtain their HIV testing results. Those who had yet to be notified were informed of possible HIV exposure and offered HIV testing. | PMC10281637 | |
Sampling procedures | From January 2020 to January 2021, we recruited 55 incarcerated men with HIV from six all‐male jail and prison facilities in Jakarta, Indonesia representing differing security levels, population sizes and inmate characteristics. Prison medical staff introduced the study to HIV‐positive inmates using a project‐prepared script before or after their regularly scheduled clinic visits. Those inmates who indicated possible interest in participating were invited to meet privately with a research team member for screening and to learn more about the study prior to being asked to give informed consent.To participate in the study, men had to be 18 years of age or older (by prison regulations), HIV positive (confirmed by HIV rapid test at enrolment), self‐reported as sexually active and/or injecting drugs during the year before incarceration, incarcerated within the last 3 years and more than 6 months away from their release date. Of the 241 inmates who were screened for possible participation, 175 were excluded from the study for having met one or more of its exclusion criteria. Of the 66 eligible inmates, 11 (15%) declined to participate due to feeling anxious or undecided about notifying partners ( | PMC10281637 | ||
Soliciting partner names and contact information | A project‐trained APN counsellor met with each inmate enrolled in the study to explain the importance of informing former sex and/or drug injection partners of possible HIV exposure and to encourage them to get tested and into treatment if needed. Each participant was asked to identify and provide contact information for those partners at HIV risk whom they might want to be notified. Index participants were allocated subsequently to one of the study's two conditions: self‐tell only (Indonesia's standard of care) or the Impart APN choice model, using a numbered sealed envelope system to conceal allocation from research staff [ | PMC10281637 | ||
Study conditions: self‐tell only notification versus Impart APN | PMC10281637 | |||
Self‐tell only notification | Participants randomized to self‐tell notification were assisted in developing a notification plan and coached in how to tell their at‐risk partners by the end of 6 weeks. They also were asked for permission to verify whom they had told or not when that period ended. Inmates could choose to tell their partner(s) by telephone, mail or in‐person during visitation at the jail/prison facility. They also could elect to have an HIV counsellor present during in‐person telling or by telephone to answer any clinical questions that the partner might have. | PMC10281637 | ||
Impart APN | Participants randomized to the Impart arm could choose per partner between sell‐tell notification or having an Impart APN‐trained nurse and community outreach healthcare provider work as a team to locate and notify their partners without revealing the identity of who had named them. With the latter choice, Impart notifiers initially contacted named partners by telephone and identified themselves as research‐affiliated health workers with important information about their health that needed to be shared in person. Partners who agreed to meet were asked to choose a location. Notification by telephone was delivered only as a last resort when circumstances prevented in‐person notification or a partner insisted on learning the reason for the telephone call. To locate partners whose contact information was unknown or could not be reached by telephone, APN notifiers visited the partner's residence, known “hang‐out spots” or other address(es) as necessary to find them. Notifiers were instructed never to reveal why they were searching for the person but only to say that they had some important information for them. Once contact was made at a private location, partners were advised of their possible shared exposure to HIV. To protect the confidentiality of incarcerated index participants, APN notifiers were given no information about the index participant and thus could not reveal their names or provide identifying information during this meeting. | PMC10281637 | ||
Partner HIV testing post notification | Partners notified by the Impart team were offered immediate HIV rapid testing using a fingerstick, combination antigen‐antibody test [ | PMC10281637 | ||
Data collection | Socio‐demographic and health information were obtained from all HIV‐positive inmates enrolled as index participants prior to randomized group assignment. Using code numbers instead of personal identifiers, research staff recorded group assignment for each index participant, the number and characteristics of partners named (gender, approximate age and mode of exposure) and Impart participants’ preference per partner for self‐tell versus APN notification. Although no compensation was given for agreeing to name or contact partners, all participants received a snack and basic toiletry kit as thanks for their time in being interviewed, even if they chose not to name or contact partners.Six weeks after the initial naming session, participants were reinterviewed about their notification experience. Participants in both arms who intended to inform one or more partners were asked to report on which (if any) they had informed. All self‐reported outcomes, including results from their verification, were entered into the project database to supplement information drawn from the logs that Impart notifiers kept recording the details and outcome of each successful and unsuccessful notification. After 6 weeks, APN was offered to notify any partner previously tried as self‐tell; however, those results are not reported here. | PMC10281637 | ||
Statistical analysis | REGRESSION, SECONDARY | Our primary analysis compared the study's two groups (self‐tell only to Impart assignment) on primary and secondary outcomes using intention‐to‐treat (ITT). All partners selected for notification were included in the analysis irrespective of group allocation or notification method. Partner notification outcomes were examined using logistic regression with robust standard errors to account for clustering due to partners having a shared index participant. Partner gender and partner type were selected beforehand as covariates.For our primary analysis, partners with missing outcomes ( | PMC10281637 | |
RESULTS | PMC10281637 | |||
Socio‐demographic characteristics of index participants ( | As shown in Table Characteristics of incarcerated men with HIV recruited as index participants (Abbreviations: ART, antiretroviral therapy; IQR, interquartile range.Three participants reported only needle‐sharing partners. | PMC10281637 | ||
Socio‐demographic characteristic of partners (117) identified for HIV notification | All partners selected for notification were included in the analysis irrespective of group allocation or notification method. Figure Study flow diagram. Abbreviation: APN, assisted partner notification Partners ranged from 17 to 56 years of age (median of 28 years) and on average were younger than the index participants who named them. Most of those named (91/117) had been exposed through sex, including as spouses and regular sex partners, while 22% (26/117) had shared drug injection equipment. Most sex partners ( | PMC10281637 | ||
HIV notification and testing outcomes | APPENDIX | Table Characteristics of partners selected for notification (Abbreviations: APN, assisted partner notification; SD, standard deviation.Partner notification and HIV testing outcomes after 6 weeks by group and notification methodTwo partners confirmed as having been notified.One partner confirmed as having been notified.None of the self‐tell partners contacted by researchers reported having been tested for HIV.The remaining 21 partners were unable to be located (Table Multivariate models predicting partner notification from intention‐to‐treat analysis (Note: All sensitivity analyses (Appendix Abbreviations: APN, assisted partner notification; CI, confidence interval; OR, odds ratio. Note: missing = failure. | PMC10281637 | |
DISCUSSION | Our research demonstrates that voluntary APN can be implemented successfully and ethically within the organizational structure of a prison setting. The Impart model's positive effects in increasing partner notification remained significant in and after adjusting for partner sex and type and even when assuming best‐case scenarios for missing verification data in the control group. The use of clinically trained notifier teams equipped to offer immediate point‐of‐contact HIV testing was successful to increase HIV testing and find new cases.In general, the motivation to inform a partner of HIV exposure can be attributed to one or more factors, including self‐perception of ethical responsibility, concerns about the partner's health or to secure social support [No one approach to partner notification works best, and a combination of different approaches is needed [Impart point‐of‐contact HIV testing also yielded a higher success rate than depending on an index person alone to encourage their partners to be tested. Of the 24 partners contacted in the Impart arm, 15 completed immediate point‐of‐contact HIV testing, of whom five were newly diagnosed and referred for treatment. Given that each partner contacted through APN was suspected or known to have been exposed to HIV, even partners who declined testing or who tested negative stood to benefit from notification counselling in HIV prevention. | PMC10281637 | ||
Limitations of the study | Limitations of the study include relatively small sample size, short duration of follow‐up and possible bias due to incorrect self‐reporting of self‐tell outcomes. Nevertheless, to our knowledge, this research represents the first and largest study to develop and evaluate an APN model for use in prison settings. We are fully aware that fewer than half of the partners who index participants reported having personally told (7/17) could be confirmed. Yet, if all such reports of successful self‐tell notifications are indeed valid, the Impart choice model still proved three to four times more effective in successfully notifying at‐risk partners and generating HIV testing than self‐tell notification alone. | PMC10281637 | ||
CONCLUSIONS | Our results confirm that the Impart APN model can be implemented successfully in jail and prison settings despite the many barriers to HIV notification that incarceration presents. With its trained team of notifiers, the model provides an effective means for HIV‐positive prisoners to inform HIV‐exposed partners whom they otherwise might not be able to reach or wish personally to tell. Although this study was conducted in Indonesia, the Impart model holds strong potential for successful implementation in other countries and with other incarcerated populations. It warrants further exploration. | PMC10281637 | ||
COMPETING INTERESTS | The authors declare no competing interests. | PMC10281637 | ||
AUTHORS’ CONTRIBUTIONS | VAE | All authors have contributed equally to the study's conceptualization and design. GJC obtained funding as Principal Investigator and wrote the initial manuscript with JL and AR. AW and AR supervised the research in Indonesia and analysed data with AS who planned the statistical analysis. VAE helped to develop the study's protocols and assessments and contributed with all authors to the interpretation of findings and revising the final manuscript. | PMC10281637 | |
FUNDING | Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under award number R34 MH115779 to GJC. | PMC10281637 | ||
Supporting information |
Click here for additional data file. | PMC10281637 | ||
ACKNOWLEDGEMENTS | We thank the study participants for their time and effort to participate in the research. We gratefully acknowledge the cooperation of the Directorate General of Corrections, Ministry of Law and Human Rights, Republic of Indonesia and their staff in conducting the study. | PMC10281637 | ||
DATA AVAILABILITY STATEMENT | Data requests referencing protocol# 2019‐0196 (PI: Culbert) may be sent to the Director of Research Facilitation at the University of Illinois Chicago College of Nursing. | PMC10281637 | ||
REFERENCES | PMC10281637 | |||
Clinical trial registration | Tixagevimab/Cilgavimab, coronavirus disease | DISEASE, DISEASE PROGRESSION, VIRUS | Edited by: Tanushree Dangi, Northwestern University, United StatesReviewed by: Kin Israel Notarte, Johns Hopkins University, United States; Diego Cantoni, MRC-University of Glasgow Centre For Virus Research (MRC), United KingdomSeveral virus-neutralizing monoclonal antibodies (mAbs) have become new tools in the treatment of the coronavirus disease (COVID-19), but their effectiveness against the rapidly mutating virus is questionable. The present study investigated the effectiveness of Tixagevimab/Cilgavimab and Regdanvimab for mild and moderate COVID-19 treatment in real-world clinical practice during the Omicron variant-dominant period. Patients with known risk factors for disease progression and increasing disease severity were enrolled in the study within the first 7 days of symptom onset. Seventy-seven patients were divided into four groups: first 15 patients received 300 mg Tixagevimab/Cilgavimab intravenously (IV) and 23 patients got the same drug 300 mg intramuscularly (IM), the next 15 patients was on the same combination in dose of 600 mg IV, and 24 patients were on Regdanvimab at a dose of 40 mg/kg IV. By Day 4, 100% of Tixagevimab/Cilgavimab IV patients showed negative polymerase chain reaction results for SARS-CoV-2 Ribonucleic acid (RNA) regardless of the mAbs dose while in the Regdanvimab group 29% of the patients were positive for SARS-CoV-2 virus RNA. The testing for virus neutralizing antibodies (nAbs) to various Omicron sublineages (BA.1, BA.2, and BA.5) showed that an increase in nAb levels was detected in blood serum immediately after the drug administration only in Tixagevimab/Cilgavimab 300 mg and 600 mg IV groups. In the group of intravenous Regdanvimab, a significant increase in the level of nAbs to the Wuhan variant was detected immediately after the drug administration, while no increase in nAbs to different Omicron sublineages was observed.
| PMC10623550 |
Introduction | Tixagevimab/Cilgavimab, coronavirus infection | CORONAVIRUS INFECTION | Vaccination against the new coronavirus infection COVID-19 has reduced morbidity, mortality and the burden on the healthcare system worldwide (We have observed a revolution in the treatment of coronavirus infection and development of passive immunity against it. Nowadays several SARS-CoV-2-specific neutralizing mAbs in use possess not only a direct antiviral effect, but also the capability for prolonged circulation underpinning their protective potential (SARS-CoV-2 actively acquires new mutations leading to the appearance of numerous new SARS-CoV-2 variants (The mAbs have demonstrated efficacy and safety in many COVID-19 clinical trials around the world (Tixagevimab/Cilgavimab was one of the first mAbs registered worldwide for COVID-19 treatment, including the Russian Federation (Due to the generalized spread of different SARS-CoV-2 Omicron sublineages, we conducted a study of the effectiveness of virus-neutralizing monoclonal antibodies (Tixagevimab/Cilgavimab [Evusheld] and Regdanvimab [Regkiron]) for the treatment of the new coronavirus infection (COVID-19) in adult patients. | PMC10623550 |
Materials and methods | PMC10623550 | |||
Study design and participants | CORONAVIRUS INFECTION | We conducted a non-randomized, single-center, prospective observational cohort study. The study was performed between August 20, 2022 and February 1, 2023 within the facilities of the multidisciplinary City Clinical Hospital No. 52 (Moscow, Russian Federation) and the N.F. Gamaleya Research Institute of Epidemiology and Microbiology (Moscow, Russian Federation). The trial was conducted in accordance with the ethical principles derived from international guidelines, including the Declaration of Helsinki, and was approved by the local ethics committee (version 1.1 of 08.09.2022). The study was registered on We included adults (18 years or older) of both sexes according to the following inclusion and exclusion criteria. Inclusion criteria were: 1) confirmed diagnosis of a new mild or moderate COVID-19 coronavirus infection ( | PMC10623550 | |
Description of medical intervention | Tixagevimab/Cilgavimab, groups:15, coronavirus infection | DISEASE PROGRESSION, VIRUS, CORONAVIRUS INFECTION, DISEASE COURSE, RECRUITMENT | The study included 77 patients diagnosed with COVID-19 as outpatients by qualitative determination of the SARS-CoV-2 antigen or SARS-CoV-2 RNA, with mild or moderate disease course and a high risk of disease progression. The severity of coronavirus infection and the risks were determined according to the Russian Interim Clinical Guidelines on COVID-19 (The scheme of patient recruitment for the study. T/C, Tixagevimab/Cilgavimab; PCR, polymerase chain reaction; IM, intamuscularly; IV, intravenously; mg, milligram; kg, kilogram; Regd, Regdanvimab; VNA, virus neutralizing antibody; CRP, C-reactive protein. Patients were admitted to the Day patient department. The patients were divided into four groups: 15 patients who received Tixagevimab/Cilgavimab IV 300 mg; 23 patients who received Tixagevimab/Cilgavimab IM 300 mg; 15 patients who received Tixagevimab/Cilgavimab IV 600 mg; 24 patients who received Regdanvimab IV at a dose of 40 mg/kg of body weight. PCR, VNA titer, lymphocyte count, PCR, fibrinogen, and D-dimer were monitored on day 0. On day 4, all the above parameters were monitored, and the outcomes were recorded.The patients were divided into four groups:15 patients who received Tixagevimab/Cilgavimab IV 300 mg.23 patients who received Tixagevimab/Cilgavimab IM 300 mg.15 patients who received Tixagevimab/Cilgavimab IV 600 mg.24 patients who received Regdanvimab IV at a dose of 40 mg/kg of body weight.No randomization was performed as it was a real world clinical study.The administration of drugs in all groups of patients was regulated by the Russian Interim Clinical Guidelines on COVID-19 (Immediately before the drug administration (Day 0) as part of routine clinical practice to assess the severity of COVID-19 all patients underwent the following tests and procedures: full blood count, biochemical blood assay (including CRP and lactate dehydrogenase [LDH]), coagulogram (including fibrinogen and D-dimer), chest СТ scan, ECG, nasopharyngeal swab for polymerase chain reaction (PCR) testing to detect SARS-CoV-2 RNA. Additionally, after signing the informed consent to participate in the study the patients also underwent blood serum sampling for the test of virus neutralization activity before the administration of mAbs and an hour after the administration of mAbs. On Day 4 after the administration of Tixagevimab/Cilgavimab or Regdanvimab the patients underwent the following tests and procedures: full blood count, biochemical blood assay (including CRP and LDH), coagulogram (including fibrinogen and D-dimer), chest СТ scan, ECG, nasopharyngeal swab for PCR testing to detect SARS-CoV-2 RNA and blood serum testing for virus neutralization activity. | PMC10623550 |
Neutralization assay | Investigations of live SARS-CoV-2 viruses were performed in BSL-3 facilities. We used the following SARS-CoV-2 sublineages for neutralization assays: B.1.1.1 (Wuhan, S:D614G hCoV-19/Russia/Moscow_PMVL-1/2020), B.1.1.529 Omicron BA.1 (hCoV-19/Russia/MOW-Moscow_PMVL-O16/2021), B.1.1.529 Omicron BA.2 (hCoV-19/Russia/MOW-PMVL-ON402/2022), B.1.1.529 Omicron BA.5 (hCoV-19/Russia/SPE-RII-25357S/2022). Viruses were propagated and titrated in Vero E6 cells. Viruses were titrated by microtitration method; titers were determined by the 50% tissue culture infective dose (TCID50) method, the titer was determined by the Spearman–Kaerber method. Determination of the neutralizing antibody levels in serum samples was performed by the microneutralization test as described earlier ( | PMC10623550 | ||
Outcomes | inflammation, death | DISEASE, INFLAMMATION, VIRUS, SECONDARY | We evaluated the laboratory efficacy, clinical results and titers of virus neutralizing antibodies (nAbs) against the Wuhan variant and Omicron sublineages BA.1, BA.2, BA.5. Primary endpoints included decrease of the positive SARS-CoV-2 PCR results on Day 4 and the nAbs increase after administration one hour and on Day 4 after administration in comparison with Day 0 (i.e. before mAbs administration).The secondary endpoints in the study included evaluation of lymphocyte concentration changes, measurement of markers of systemic inflammation (CRP, fibrinogen, D-dimer) on Day 4 of observation, and the outcome of the disease (discharge, hospitalization, death). | PMC10623550 |
Statistical analysis | Principles for calculating the sample size: no preliminary calculation of the required sample size was carried out. Statistical data analysis: nonparametric methods of descriptive statistics were used. The median and interquartile range (IQR) were determined; the geometric mean was used in the description of relative values over time. The data analysis was performed using the IBM SPSS STATISTICS v.22 statistical program package. To compare quantitative data, the Mann–Whitney U-test and the Kruskal–Wallis test were used depending on the number of groups being compared; Pearson’s χ2 test was used for categorical data. Spearman’s rank correlation coefficient was used to compare nonlinear indicators. The differences were considered significant at p<0.05. | PMC10623550 | ||
Results | PMC10623550 | |||
Description of patients and laboratory indicators | DM, comorbidity, Gastric ulcer disease, COPD | ISCHAEMIC HEART DISEASE, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, DIABETES MELLITUS, COPD, IHD, ATRIAL FIBRILLATION | The general characteristics of COVID-19 patients admitted to the day patient facility for antiviral therapy are presented in General patient data.IV, intravenously; IM, intramuscularly; F, female; M, male; BMI, body mass index; mg, milligram, kg, kilogram.Quantitative data are presented as median and interquartile range (Q1-Q3).The frequency of comorbidities in the general group of patients. COPD, Chronic obstructive pulmonary disease; KAT, kidney allotransplantation; IHD, ischaemic heart disease; A-Fib, atrial fibrillation; DM, Diabetes Mellitus; GUD, Gastric ulcer disease. All groups had high levels of comorbidity.All patients were vaccinated with Gam-COVID-Vac. The frequency of vaccination was not significantly different between groups (p = 0.5). The duration between vaccine and mab administration was also not significantly different between groups.Most of the patients were admitted to the day patient facility on Day 3 after the onset of symptoms. During the observation period the condition of the patients in all groups was stable, and the body temperature was in the normal range.SARS-CoV-2 RNA PCR testing showed that 100% patients in the Tixagevimab/Cilgavimab IV groups tested negative at Day 4 of the study regardless of the dose, while 29% of patients in the Regdanvimab group tested positive for SARS-CoV-2 RNA, which was significantly higher (p=0,017) (Testing for SARS-CoV-2 RNA by real-time PCR in nasopharyngeal swabs. IM, intamuscularly; IV, intravenously. SARS-CoV-2 RNA PCR testing showed that 100% patients in the Tixagevimab/Cilgavimab IV groups tested negative at Day 4 of the study regardless of the dose, while 29% of patients in the Regdanvimab group tested positive for SARS-CoV-2 RNA, which was significantly higher. | PMC10623550 |
Levels of virus-neutralizing antibodies | Tixagevimab/Cilgavimab, ground-glass opacities | DISEASE, VIRUS, SECONDARY | The study was conducted during the surge of the SARS-CoV-2 Omicron BA.5 sublineage. Genetic analyses of the patients’ nasopharyngeal swabs by real-time PCR confirmed that all swabs contained SARS-CoV-2 Omicron sublineage BA.5 RNA.We determined the levels of nAbs to the initial SARS-CoV-2 variant (Wuhan D614G) and to the Omicron sublineages BA.1, BA.2 and BA.5 in the blood serum of the patients to identify the neutralization activity of nAbs. In the IV treatment groups (Tixagevimab/Cilgavimab 300 mg, Tixagevimab/Cilgavimab 600 mg and Regdanvimab groups), we observed a strong increase in nAbs to the Wuhan variant immediately after the drug administration (Titers mAbs to different SARS-CoV-2 variants.IV, intravenously; IM, intramuscularly; mg, milligram, kg, kilogram; GMT, geometric mean titer; CI, confidence interval.Interestingly, in the Tixagevimab/Cilgavimab IM 300 mg group the levels of nAbs to the Omicron sublineages reached its maximum by Day 4 of the study, with values significantly higher than those in the Regdanvimab group (also on Day 4). It is important to note that the levels of nAbs to different Omicron sublineages did not differ significantly on Day 4 between the groups of IV and IM administration of Tixagevimab/Cilgavimab at a dose of 300 mg.Analysis of the nAb levels to different SARS-CoV-2 sublineages over time within each group revealed the following patterns:Tixagevimab/Cilgavimab IV administration groups: a significant increase in the levels of nAbs to the Wuhan and Omicron BA.1 and BA.2 sublineages was detected immediately after the drug administration, the nAb levels remained stable for 4 days; a significant increase in the levels of nAbs to the Omicron BA.5 sublineage was detected immediately after drug administration, and then the nAb levels increased over time and reached their maximum on Day 4 of the study, which indicated the development of the host immune response.Tixagevimab/Cilgavimab IM administration group: the highest nAb levels were detected on Day 4 of the study. At the same time, the levels of nAbs to the Omicron sublineages on Day 4 of the study did not differ between the groups of IV and IM administration.Regdanvimab IV administration group: a significant increase in the levels of nAbs to the Wuhan variant was detected immediately after administration, while there was no increase in nAbs to different sublineages of the Omicron variant. On Day 4 of the study, a decrease in nAbs to the Wuhan variant was detected, indicating the removal of nAbs from the systemic circulation. The increase in nAbs to the Omicron sublineages on day 4 of the study indicates the development of immune response.In the groups that received Tixagevimab/Cilgavimab the levels of nAbs to the Omicron sublineage BA.5 on Day 4 of the study were significantly higher (about 10 times) than in the Regdanvimab group.The levels of nAbs to the Omicron BA.1, BA.2 and BA.5 sublineages in the intravenous Tixagevimab/Cilgavimab group were significantly higher than those in the Regdanvimab group. A robust increase in nAbs to the Wuhan variant of SARS-CoV-2 virus was detected in patients who received Regdanvimab immediately after administration, while no increase of nAb levels to the Omicron BA.1, BA.2 and BA.5 sublineages was seen (Comparison of nAbs levels in the IV Tixagevimab/Cilgavimab and IV Regdanvimab patient groups. T/C, Tixagevimab/Cilgavimab; Regda, Regdanvimab. The levels of nAbs to the Omicron BA.1, BA.2 and BA.5 sublineages in the intravenous Tixagevimab/Cilgavimab group were significantly higher than those in the Regdanvimab group. A robust increase in nAbs to the Wuhan variant of SARS-CoV-2 virus was detected in patients who received Regdanvimab immediately after administration, while no increase of nAb levels to the Omicron BA.1, BA.2 and BA.5 sublineages was seen.The nAb titer for the Wuhan variant in patients who received Tixagevimab/Cilgavimab IV exceeded 10,000; the nAb titer for the Omicron BA.5 sublineage Tixagevimab/Cilgavimab group on Day 4 of the study was 450, with a greater than 22-fold decrease in the neutralization activity when compared to the Wuhan variant. The levels of nAbs to Omicron BA.2 and BA.5 sublineages in the Tixagevimab/Cilgavimab IM group were significantly higher by Day 4 than in the Regdanvimab group (Comparison of nAbs levels in IM Tixagevimab/Cilgavimab and Regdanvimab patient groups. T/C, Tixagevimab/Cilgavimab; Regda, Regdanvimab; IM, intramuscularly. The levels of nAbs to Omicron BA.2 and BA.5 sublineages in the Tixagevimab/Cilgavimab IM group were significantly higher by Day 4 than in the Regdanvimab group.The increase in the nAb titer in the blood serum of patients who received Tixagevimab/Cilgavimab IM occurred with a delay (compared to IV administration). However, by Day 4 of observation the levels of nAbs to Omicron BA.1, BA.2, BA.5 sublineages did not differ from the Tixagevimab/Cilgavimab IV group (Comparison of nAbs levels in IV and IM Tixagevimab/Cilgavimab patient groups. IM, intamuscularly, IV, intravenously. The increase in the nAb titer in the blood serum of patients who received Tixagevimab/Cilgavimab IM occurred with a delay (compared to IV administration). By Day 4 of observation the levels of nAbs to Omicron BA.1, BA.2, BA.5 sublineages did not differ from the Tixagevimab/Cilgavimab IV group.
Geometric mean of nAbs titers to different variants of SARS-CoV-2. In the Regdanvimab group, the geometric mean of nAb titers to the Wuhan variant was higher than that in the Tixagevimab/Cilgavimab groups, both one hour after administration and on Day 4 (p<0.001), while an inverse effect was observed for the concentrations of nAbs against Omicron sublineages (p<0.001).When analyzing the outcome of the disease as a secondary endpoint, 100% recovery was observed in the Tixagevimab/Cilgavimab groups regardless of the route of administration. In the Regdanvimab group, 2 patients (8.3%) were transferred from the day patient facility to the hospital inpatient department due to the appearance of new foci of ground-glass opacities seen on chest CT, as well as the absence of positive laboratory dynamics. However, the difference between the groups was not statistically significant (p =0,209) (Outcomes of the disease.IM, intamuscularly; IV, intravenously; mg, milligram; kg, kilogram.The study of laboratory parameters over time showed that the lymphocyte levels did not differ significantly between patients, while the levels of CRP and D-Dimer were significantly lower in the Tixagevimab/Cilgavimab 300 + 300 mg IV group by Day 4 of the observation than in the other groups regardless of the ongoing concomitant anti-inflammation therapy (Laboratory parameters over time. CRP, C-reactive protein; IM, intamuscularly, IV, intravenously, mg, milligram, kg, kilogram; Regd, Regdanvimab. The lymphocyte levels did not differ significantly between patients, while the levels of CRP and D-Dimer were significantly lower in the Tixagevimab/Cilgavimab 300 + 300 mg IV group by Day 4 of the observation than in the other groups regardless of the ongoing concomitant anti-inflammation therapy. | PMC10623550 |
Discussion | Tixagevimab/Cilgavimab, tixagevimab/cilgavimab | SYSTEMIC INFLAMMATORY RESPONSE, PROGRESSION | During COVID-19 pandemic, SARS-CoV-2 was rapidly acquiring new mutations with the wide spread of new variants among the world population. At the start of our research in September 2022, the Omicron variant consisted of 5 main sublineages, BA.1, BA.2, BA.3, BA.4, and BA.5 (According to our previous study from February 2022, when the epidemiological data suggested the beginning of the Omicron surge, the use of mAb Regdanvimab led to a significant decrease in the severity of clinical manifestations according to the Clinical Progression Scale (Despite the persistent virus-neutralising activity of tixagevimab/cilgavimab against the Omicron variant, it was still reduced by 22-fold compared to the Wuhan variant. The decrease of virus-neutralizing activity against Omicron is confirmed by literature data. Cao et al. reported that the activity of Bamlanivimab/Etesevimab, Casirivimab/Imdevimab, and Tixagevimab/Cilgavimab was significantly weakened against BA.2.12.1, BA.4, and BA.5 Omicron sublineages, while Sotrovimab was still active, but with reduced effectiveness (In our study, effective viral-neutralizing activity against the variants mentioned above was demonstrated by the negative results of PCR testing for SARS-CoV-2 RNA on Day 4 in the Tixagevimab/Cilgavimab groups being significantly more frequent than that in the Regdanvimab group (p < 0.017). PCR results in the Tixagevimab/Cilgavimab IV groups were 100% negative regardless of the dose used. It was also noted that the systemic inflammatory response, namely the levels of CRP and D-dimer, was significantly lower by Day 4 in the Tixagevimab/Cilgavimab 600 mg IV group than in other groups regardless of the concomitant anti-inflammatory therapy.Upon IM administration of Tixagevimab/Cilgavimab, there was no increase in nAb titers immediately after administration due to the pharmacodynamics of mAbs, unlike with the IV administration. The nAb testing in this study was performed one hour after the drug administration and then on Day 4. The concentrations of mAbs in the Tixagevimab/Cilgavimab groups one hour after the administration were higher in the IV groups than those in the IM group, and became equal by Day 4, which is consistent with publication data ( | PMC10623550 |
Conclusion | Tixagevimab/Cilgavimab | Tixagevimab/Cilgavimab, in contrast to Regdanvimab, demonstrated higher nAbs titers to BA.1, BA.2, and BA.5 Omicron sublineages, as well as better laboratory efficacy and clinical results by Day 4 after the drug administration. The IV route of administration of Tixagevimab/Cilgavimab was associated with greater efficiency due to the faster effect. However, when compared with the nAbs titers to the Wuhan strain, a 22-fold decrease in virus-neutralizing activity was demonstrated, which suggests a possible loss of drug effectiveness due to the further mutations of SARS-CoV-2. Such rapid mutation makes it necessary to introduce new technologies into mAbs research and development. | PMC10623550 | |
Limitations | VIRUS | Limitations of this study include the lack of evaluation of virus neutralizing activity of serum after 4 days post-injection. There is also no evaluation of the effect of administered virus neutralizing antibodies on the development of long COVID-19. | PMC10623550 | |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10623550 | ||
Ethics statement | The studies involving humans were approved by Local ethics committee City Clinical Hospital 52 (version 1.1 of 478 08.09.2022). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. | PMC10623550 | ||
Author contributions | MSL: Writing – original draft, Writing – review & editing. DF: Writing – original draft, Writing – review & editing. AI: Writing – original draft. AKo: Writing – original draft. AS: Writing – original draft. SA: Writing – original draft. AC: Writing – original draft. ID: Writing – original draft, Writing – review & editing. TK: Writing – original draft. GA: Writing – original draft. AT: Writing – original draft. DS: Writing – original draft. AKa: Writing – review & editing. MAL: Writing – review & editing. DL: Writing – review & editing. AG: Writing – review & editing. | PMC10623550 | ||
Acknowledgments | This study is supported by local Research Ethics Committee of Clinical City Hospital 52 (version 1.1 of 08.09.2022). | PMC10623550 | ||
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10623550 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10623550 | ||
References | PMC10623550 | |||
Introduction | pulmonary embolism, thrombosis, bleeding, thrombo-embolic, cancer, VTED, digestive cancer, venous thrombosis | PULMONARY EMBOLISM, THROMBOSIS, BLEEDING, DEEP VEIN THROMBOSIS (DVT), BLOOD CLOTS, VENOUS THROMBOEMBOLIC DISEASE, CANCER, EVENT, DIGESTIVE CANCER, VENOUS THROMBOSIS, POSTOPERATIVE THROMBOSIS, BSE | Venous thromboembolic disease (VTED) refers to a condition characterized by the formation of blood clots within the veins, commonly has two main clinical presentations: deep vein thrombosis (DVT) and/or pulmonary embolism (PE) [The high risk of postoperative thrombosis is due to the combination of two risk factors: cancer and major surgery [Several prospective randomized studies conducted in the early 1980s and late 1990s showed that thromboprophylaxis reduces the risk of thrombosis compared to no prophylaxis or placebo [Over the years, several molecules have been introduced on the market: unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonist (VKA) and direct oral anticoagulants (DOACs). Several guidelines have recommended LMWH or UFH in major abdominopelvic surgery in the absence of bleeding risk [LMWH has advantages over UFH such as a longer half-life and predictable bioavailability [Several biosimilar versions of LovenoxThis study aimed to compare a Biosimilar Enoxaparin [BSE] with Branded Enoxaparin [BE] in patients undergoing digestive cancer surgery in the prevention of venous thrombosis in the postoperative period, to compare the safety of the two treatments and to identify the factors predictive of thrombo-embolic event. | PMC10619849 |
Materials and methods | cancers of the abdomen, disorder of haemostasis, bleeding, chronic renal failure, thrombosis, intraoperative bleeding, death, WBH.8, tumours, ICH, cancer, digestive cancer, Digestive cancers, diabetes, cardiovascular disease, CRF, thrombotic | BLEEDING, CHRONIC RENAL FAILURE, CRF, REGRESSION, EVENTS, INTRAOPERATIVE BLEEDING, THROMBOSIS, DEEP VEIN THROMBOSIS, CANCER, RESPIRATORY FAILURE, BLIND, POLYCYTHAEMIA, RENAL FAILURE, DIGESTIVE CANCER, DISEASE, COMPLICATIONS, THROMBOEMBOLIC EVENT, TUMOURS, EVENT, HEPARIN-INDUCED THROMBOCYTOPENIA, DISEASE, SECONDARY, DISORDER OF HAEMOSTASIS, BSE | This is a prospective, comparative, randomized study, conducted in a single centre during four years and nine months: from October 12, 2015, to July 08, 2020.1. Patients:Included patients were: 1) over 18 years of age with proven, known or newly diagnosed, operable digestive cancer regardless of its nature, location, or stage, 2) and all patients who underwent emergency or elective surgery. Non-included patients were: 1) participating in another study, 2) patients with prior unfractionated heparin impregnation in the last 30 days, 3) patients with chronic renal failure with creatinine clearance<30 ml/min, 4) patients with a known history of peripheral and/or deep vein thrombosis occurring within three months prior to study inclusion, 5) patients under anticoagulation treatment within the last three months, 6) patients with a known disorder of haemostasis, 7) patients unwilling to participate in this study or unable to understand its objectives, 8) and patients with a pregnancy occurring during the study were not included. The follow-up of the included patients was done according to the CONSORT guidelines [2. Disease:Digestive cancers (oesophagus, stomach, small bowel, colon, rectum, hepatobiliary and pancreas) in an early or advanced stage, complicated or not, were included. Extra-digestive cancers of the abdomen and patients with tumours without histological confirmation were not included.3. Treatment:According to randomization the patient received Branded Enoxaparin (BE) (Lovenox4. Outcome measures:The primary endpoint was any asymptomatic thromboembolic event, assessed by a systematic Doppler ultrasound of the vessels of the lower limbs between day-7 and day-10 post surgery. This evaluation was done in a blinded fashion. The sonographer was not aware of the patients’ randomization. The secondary endpoints were the occurrence of a symptomatic thrombotic event, the occurrence of incident heparin-induced thrombocytopenia, the occurrence of bleeding events and mortality.5. Calculation of sample size and randomizationThe occurrence of subclinical thrombosis postoperatively after digestive cancer surgery is estimated to be 18% [The database used the same validated electronic data capture system (DACIMA), which complies with FDA 21 CFR part 11 (Food and Drug Administration 21 Code of Federal Regulations part 11), HIPAA (Health Insurance Portability and Accountability Act) & ICH (International Conference on Harmonization) requirements.6. Compliance, Protocol Violation, Patient follow-upCompliance was defined as the number of days enoxaparin was taken. Days not taken were reported in relation to the previously planned number of days of intake and were secondarily translated into percentage. It was considered "nonadherence" if the rate of non-take days ≥20%. Protocol violation was defined by any selected patient who had "nonadherence" to study treatment ≥20%, randomization allocation error, and Doppler ultrasound performed outside the 7- to 10-day postoperative interval.Several follow-up visits were performed. An inclusion visit verified the eligibility of patients and included them if they met the selection criteria. The patient is hospitalized for seven to 10 days. Ultrasound and clinical control were performed between post-operative day seven to 10.A 30-day follow-up visit for a clinical check-up and closure of the study was planned for each patient.7. Data collection:Eighty eight variables were culled, divided into: 1) Inclusion criteria: age over 18 years, proven cancer, indication for surgical treatment, preventive administration of Enoxaparin BSE or BE, 2) Demographic variables: age, gender, weight, height, body mass index (BMI), comorbidities (history of thrombosis, diabetes, cardiovascular disease, respiratory failure, renal failure, corticosteroid therapy, immunosuppression, polycythaemia, postpartum); 3)Preoperative variables: date of disease discovery, nature of the cancer, site, extension work-up, biology, preoperative chemotherapy, preoperative radiotherapy, 4) Intraoperative variables: operative time, nature of the procedure, type of anaesthesia, intraoperative bleeding; and 5) Postoperative variables: treatment (dose, date of administration, duration), biological follow-up during the study, Doppler ultrasound (date, result), subclinical and clinical thromboembolic events, bleeding event, heparin-induced thrombocytopenia, death, follow-up visit (1 month), All data have been collected by WD and WBH.8. Statistical analysis:All data were entered into SPSS® statistical software (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.).Qualitative variables were expressed by their frequency and percentages. Quantitative variables were mentioned by the mean and standard deviation when the distribution was Gaussian and by the median with extremes and interquartile range when the distribution variable was not Gaussian.The comparison of BSE versus BE groups was performed by independent groups Student’s t-test or the non-parametric Mann-Whitney U test for continuous variables. Categorical variables were compared by Pearson’s chi-squared test or Two-sided Fisher’s exact test, when appropriate. The margin of equivalence, estimated as the difference in frequencies, was between -0.20 and +0.20 (difference in proportion is 0.20). The real difference would be 0.00. The calculation assumes the performance of a one-sided Student’s t-test. The 95% confidence intervals were compared graphically with the equivalence margin interval. The value of p≤0.05 was considered the threshold for significance.We performed a prognostic study to identify independent predictors of clinical and subclinical thrombosis. We performed a crude bivariate analysis using appropriate statistical tests. Factors that were accompanied by a value of p≤0.05 were entered into a Backward logistic regression model. Each retained factor was accompanied by its relative risk and 95% confidence interval with the p value.9. Disclosure, Trial registrationThe Médis laboratory provided the BE treatment and sponsored the practice of Doppler ultrasound exams. The study was carried out in accordance with the current version of the Helsinki Declaration (52nd WMA General Assembly, Edinburgh, Scotland, October 2000). The clinical trial was conducted in accordance with the guidelines of the International Conference on Harmonization (ICH) on Good Clinical Practice (GCP). All patients provided written informed consent to participate in the study before being included.The patient information sheet details the procedures involved in the study (objectives, methodology, potential risks, expected benefits) and the investigator explains them to each patient. The patient signed the consent form to indicate that the information had been explained and understood. The patient was then given time to review the information presented before signing and dating the informed consent form to indicate that he fully understood the information and volunteered to participate in the study. The trial was registered on CLINICALTRIALS.GOV under the number NCT02444572.10. Practical conduct:After patient’s admission in the surgical department B of Charles Nicolle Hospital, a number was assigned to the medical record. The intern in charge of the patient wrote the patient’s medical record, specifying the address and telephone number, under the supervision of the resident and the senior physician in charge. Once it was verified that the patient was eligible to be included in the study, a balanced randomization was done on the same day using the DACIMA software. The person in charge of randomization was CD (one of the authors). The treatment was started eight hours after the end of the operation if there was no bleeding.Once the ultrasound was done between the seventh and 10th postoperative day, the patient was discharged except when he/she had complications requiring a prolonged hospitalization. The randomization is set automatically by the validated IWRS (DACIMA tool). The allocation sequence was designed at the CRF development step before study kick-off. The data-manager who performed the CRF building, and the randomization sequence allocation wasn’t involved in the study management. The data collection at site level was performed by study coordinators and investigators who were aware about the allocated treatment after running the IWRS, when eligibility criteria were verified, and the subject had been available for randomization. As the protocol was an open labeled randomized, rater blind, clinical trial, only the ultrasounds specialist was unaware about the treatment allocation. The person performed the randomization were involved in the data collection. | PMC10619849 |
Results | PMC10619849 | |||
Comparability of groups | DIGESTIVE CANCER | Over four years and nine months, 168 eligible patients, had been operated in the surgical department B of Charles Nicolle Hospital for digestive cancer. Of 188 patients enrolled to participate in the study ( | PMC10619849 | |
Screening, randomization, and follow-up of study participants. | thrombosis | THROMBOSIS | No statistically significant difference was found in patients demographics and thrombosis factors ( | PMC10619849 |
Comparative study: Demographic variables (branded enoxaparin vs biosimilar enoxaparin groups). | BSE | * SD: Standard Deviation BE: Branded Enoxaparin BSE: Biosimilar Enoxaparin.# Student’s t-test or ## the non-parametric Mann-Whitney U test used for comparison of continuous variables.Categorical variables were compared by $ Pearson’s chi-squared test or $ $ Two-sided Fisher’s exact test, when appropriate.There was also no statistically significant difference between the two groups for the pre and intraoperative variables ( | PMC10619849 | |
Comparative study: Pre and intraoperative variables (branded enoxaparin vs biosimilar enoxaparin groups). | Median [ext] = Median [extreme].# Student’s t-test or## the non-parametric Mann-Whitney U test used for comparison of continuous variables.Categorical variables were compared by $ Pearson’s chi-squared test or $ $ Two-sided Fisher’s exact test, when appropriate. | PMC10619849 | ||
Rate of thromboembolic events | BSE | Seventy-one patients (87.7%) in the BE group had an ultrasound scan during the study and seventy-four patients (85.1%) in the BSE group with no statistically significant difference between the two groups (p = 0.625) ( | PMC10619849 | |
Equivalence between branded enoxaparin and biosimilar enoxaparin. | deaths, death, postoperative bleeding | BSE, HEPARIN-INDUCED THROMBOCYTOPENIA, POSTOPERATIVE BLEEDING, COMPLICATION | The number of patients who developed a post-operative complication was 14 (17.3%) in the BE group and eight (9.2%) in the BSE group (p = 0.120). Two patients (2.5%) had postoperative bleeding in the BE group and one patient (1.1%) had postoperative bleeding in the BSE group (p = 0.610). No incident of heparin-induced thrombocytopenia was mentioned in BE group and one incident occurred in BSE group (p = 1.000). There were six deaths (7.4%) in the BE group and 11 deaths (12.6%) in the BSE group without statistically significant difference between the two groups (p = 0.261). The median time to death was 10 days [6.25–14.25] in the BE group and 16 days [ | PMC10619849 |
Risk factors of clinical and subclinical thrombosis events | venous thrombosis | VENOUS THROMBOSIS | The crude bivariate analysis showed no statistically significant difference between the two groups of patients regarding the occurrence of venous thrombosis postoperatively (Tables | PMC10619849 |
Demographic variables predicting clinical and subclinical thrombosis (crude bivariate analysis). | SD = standard deviation—# Student’s t-test or## the non-parametric Mann-Whitney U test used for comparison of continuous variables.Categorical variables were compared by $ Pearson’s chi-squared test or $ $ Two-sided Fisher’s exact test, when appropriate. | PMC10619849 | ||
Pre- and intra-operative variables predictive of clinical and subclinical thrombosis (crude bivariate analysis). | POSTOPERATIVE THROMBOSIS | SD = standard deviation.# Student’s t-test or## the non-parametric Mann-Whitney U test used for comparison of continuous variables.Categorical variables were compared by $ Pearson’s chi-squared test or $ $ Two-sided Fisher’s exact test, when appropriate.There were no predictors of postoperative thrombosis after digestive oncology surgery in this study. | PMC10619849 | |
Discussion | postoperative thromboembolic | THROMBOEMBOLIC EVENT, ADVERSE EVENTS, HEPARIN-INDUCED THROMBOCYTOPENIA, POSTOPERATIVE THROMBOSIS, BSE | Our randomized clinical trial showed that there was no statistically significant difference between BE and BSE groups in the occurrence of postoperative thromboembolic events. There was no statistically significant difference between BE and BSE groups regarding incident heparin-induced thrombocytopenia. No predictors factors of postoperative thrombosis after digestive oncology surgery were identified.Our RCT is the first to compare BE with BSE on an asymptomatic thromboembolic event as the primary end point, while controlling for adverse events.A biosimilar drug is a biological drug with the same qualitative and quantitative composition in active substance and the same pharmaceutical form as a reference biological drug. A biosimilar is not regarded as a generic of a biological medicine [A systematic review, reported by Mielke et al in 2018 [As concerns Generic, several randomized controlled trials (RCT) [As concerns biosimilar, two RCTs compared new biosimilar treatment of Enoxaparin to a reference treatment [In Tunisia, the same BSE, evaluated in our RCT, has already been the subject of two non-comparative studies concerning patients who underwent a total hip replacement [The cost difference between BSE ($2.85/day) and BE ($4.5/day) is assessed over a 30-day period. Our research demonstrates that BSE offers a significant cost advantage, with daily savings of $1.65 per patient and a percentage difference of approximately -36.67%. These highlight the economic benefits associated with choosing the BSE option, reinforcing its potential as a cost-effective alternative in clinical practice. | PMC10619849 |
Predictive factor for thromboses | thrombosis, cancers, cancer, thrombocytopenia, tumour, non-thrombosis, sepsis, postoperative haemorrhage, weight loss | THROMBOSIS, THROMBOEMBOLIC EVENT, CANCERS, POSTOPERATIVE COMPLICATIONS, ADVERSE EVENTS, CANCER, THROMBOCYTOPENIA, TUMOUR, SEPSIS, POSTOPERATIVE HAEMORRHAGE, POSTOPERATIVE THROMBOSIS, BSE | In this study, there were no predictors of postoperative thrombosis after digestive oncology surgery between the thrombosis and non-thrombosis groups. This was probably due to the relatively low number of thromboembolic events. In the literature, several factors for thrombosis have been determined: patient-related factors, factors related to cancer and associated treatment factors. Indeed, the incidence of thrombosis increases in cancer patients over 80 years, whereas for certain cancers (pancreas, mesothelial tumour, and lung) [A cohort study, conducted between 2012 and 2016, identified risk factors for thrombosis during hospitalization (advanced age, male gender, steroid use, significant weight loss, preoperative sepsis, prolonged operative time, emergency surgery, and impaired general condition) and risk factors after discharge (steroid use, preoperative sepsis, postoperative complications, and impaired general condition) [As concern BSE safety patients, although the overall mortality rate of 10,1% was high in our study, there was no statistically significant difference between the two groups BSE and BE (12.6% vs 7.4%, p = 0.261). Similarly, there was no statistically significant difference between the two groups with respect to adverse events. The rate of postoperative haemorrhage was 1.1% in the BSE group and 2.5% in the BE group (p = 0.610). The rate of thrombocytopenia was 1.1% in the BSE group and zero percent in the BE group (p = 1.000).Our RCT placed great importance on its methodology by trying to predefine all the points before starting the trial. However, this RCT had some limitations: 1) It might have been more pragmatic to consider both asymptomatic and symptomatic thrombosis at the same time as primary end point, which would probably have reduced the number of subjects needed to be included. 2) Moreover, the assumption that the primary endpoint would be reached by 18% of patients [ | PMC10619849 |
Supporting information | PMC10619849 | |||
CONSORT 2010 checklist of information to include when reporting a randomised trial*. | (DOC)Click here for additional data file.(DOCX)Click here for additional data file.(DOCX)Click here for additional data file.We thank Mr Rabii Razgallah for his assistance during redaction of protocol and made available to us DACIMA platform.We thank Mrs Marwa Naimi for revising the English of the manuscript. | PMC10619849 | ||
References | PMC10619849 | |||
Background | PDO, NMIBC | In intermediate-risk non-muscle invasive bladder cancer (NMIBC) clinical guidelines suggest an adjuvant instillation with a chemotherapeutic agent. However, the agent and regimen are not clearly defined. Worldwide, less than 15% of patients receive this adjuvant chemotherapeutic instillation. We recently developed a pipeline for the generation of patient derived organoids (PDO) in NMIBC. In this phase II trial, we aim to use our in vitro pipeline to select the most effective drug for chemotherapeutic instillation in NMIBC patients. | PMC10176900 | |
Methods | tumor, bladder tumor, NMIBC, PDO, TURBT | TUMOR, BLADDER TUMOR | Patients with first diagnosis of intermediate-risk NMIBC that are directed to transurethral resection of bladder tumor (TURBT) are enrolled. During TURBT, tumor is sampled, and specimens are directed to generate PDO. Once the PDO are formed, drug screens on them for Epirubicin, Mitomycin C, Gemcitabine and Docetaxel are performed. The drug with the highest antitumor activity in vitro will then be selected for 6 adjuvant intravesical instillations once weekly. Thereafter, patients are followed according to clinical guidelines by cystoscopy. | PMC10176900 |
Keywords | PMC10176900 | |||
Background | cancers, tumor, bladder tumor, genitourinary malignancy, TURBT, Bladder cancer, bladder cancer | CANCERS, TUMOR, BLADDER TUMOR, RECURRENCE, DISEASE, PROSTATE, BLADDER CANCER, BLADDER CANCER, PRIMARY TUMOR | Bladder cancer is one of the most common cancers in the Western World and the second most common genitourinary malignancy [Prior to the final histological diagnosis during a transurethral resection of the bladder tumor (TURBT) patients undergo a cystoscopy and cytological analysis. Depending on the macroscopical results during cystoscopy and TURBT (invasion, tumor size, single/multiple), as well as the histological diagnosis (high grade/low grade) and the age of the patient, bladder cancer is stratified into low-, intermediate-, high- and very-high risk groups [Patients with low-risk disease undergo an early single adjuvant instillation of a chemotherapeutical agent [Early instillation, induction cycle and maintenance for one year of chemotherapy into the bladder is recommended for intermediate-risk NMIBC by EAU guidelines. Despite the optimal schedule and duration of further intravesical chemotherapy instillation is not defined, it should not exceed one year [There is no specific regimen for intravesical chemotherapy defined by the recent EAU-Guidelines [Until recently, the treatment of bladder cancer, for several years, was limited to surgery and to immunotherapy or chemotherapy. Currently, the extensive analysis of molecular alterations has led to novel treatment approaches [Patient derived organoids (PDO) represent the molecular aspects of the primary tumor and can not only be used to understand the biological basis of the disease, but may also be used to develop new treatment strategies. Organoids are nowadays used for research of different cancers. In the field of urology, there are studies/reports on kidney, prostate, and bladder organoids [Taken together, adjuvant intravesical chemotherapy is considered to reduce the recurrence risk of intermediate-risk bladder cancer. A clearly defined regime of therapy induction and maintenance is still lacking but should not exceed one year. The heterogeneity of non-muscle invasive bladder cancer is related to a high variability of efficacy of chemotherapeutic agents. Even though Epirubicin and MMC are the most frequently used drugs for adjuvant instillation therapy, Docetaxel and Gemcitabine show promising results in existing studies. In vitro drug screens in PDO may predict the response of the agent in vivo, but the implementation of in vitro drug screens in PDO in clinical settings are still pending. | PMC10176900 |
Methods/design | PMC10176900 | |||
Study aim and objectives | The aim of this trial is to test the possibility of using drug screens in PDO to guide intravesical instillation. | PMC10176900 | ||
Overall objective | NMIBC | Currently, the drug for chemotherapeutic instillation after TURBT in patients with intermediate-risk low grade NMIBC is selected based on doctors’- and institutional preferences. Most frequently, Epirubicin or MMC are used. Currently, no comparative studies focus on this patient population between the different drugs and the selection is not based on biological characteristics.We aim to establish a workflow into the clinical routine, that allows a specific selection of the instilled drug based on molecular characteristics of the respective NMIBC.The current study will test the use of drug screens in PDO for the prediction of treatment in patients. Therefore, we will test the implementation of drug screen in PDO in the workflow of the daily routine. | PMC10176900 | |
Primary objective | The primary objective of this study is to evaluate the rate of successful drug selection by using drug screens in PDO generated from patients with low grade intermediate-risk NMIBC. This will allow to determine the rate of patients in which drug selection can successfully be performed for adjuvant intravesical instillation therapies. | PMC10176900 | ||
Secondary objectives | RECURRENCE | Secondary objectives of the trial are to evaluate the rate of recurrence, the recurrence free survival and the progression free survival in this population. Further quality of life and safety of instillation will be assessed. | PMC10176900 | |
Ethical approval and consent | The GAIN-INST Trial (NCT05024734) has been approved by swissethics and the district ethical board from Bern (BASEC ID 2021-02369). All included patients have read the study information and signed the informed consent for this trial. | PMC10176900 | ||
Enrollment and trial design | amenorrhea | The Department of Urology at the Hospital Center in Biel is conducting the GAIN-INST Trial in which from September 2022 for two years, patients with intermediate-risk NMIBC are recruited according to the criteria in Table Inclusion and exclusion criteriaFemale subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 6 months after the last treatment. Note: Women not of childbearing potential are defined as:postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.) OR have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR has a congenital or acquired condition that prevents childbearingTrial design | PMC10176900 | |
Sample size | PDO | The alternative hypothesis states that a successful drug prediction using drug screens in PDO is possible in more than 65% of cases. Sample size was determined using a one sample test. The null hypothesis that a drug prediction will only be possible in 65% of patients will be tested against a one-sided alternative (that the proportion is larger than 65%). Assuming that the real proportion is 85%, a sample of 31 participants should show a statistically significant result at 5% significance and 80% power using an exact binomial test. Assuming an early termination of 10% of patients, a total number of 34 patients will have to be included. Thus, the study will recruit 31 patients that have completed the full 6 instillation cycles. | PMC10176900 | |
Tissue sampling, PDO generation and drug treatment | PDO | COLD | During surgery, cold cup biopsies will be harvested, digested to single cells and plated organoids are allowed to form. Thereafter, PDO are dissociated to single cells, plated and formed after 48 h. These PDO are then exposed to the compounds in the following conditions: untreated (medium) or treated (0.1% DMSO vehicle control, and 4 drugs that are currently used for intravesical instillation (Epirubicin, Mitomycin C, Gemcitabine and Docetaxel). Compound effect is then measured after 48 h by the CellTiterGlo 3D reagent from Promega measuring luminescense. For intravesical instillation, only these four drugs will be used. However, in-vitro testing will eventually include other compounds, dependent on the number of PDO available. | PMC10176900 |
Readout, drug selection and instillation | Each condition will be investigated in triplicates; triplicates and average will be used for drug selection. Only drugs that reduce viability by 50% or more compared to the vehicle, will be considered. In case that more than one drug reduces viability by 50% or more compared to the vehicle, a pairwise Wilcoxon test will be performed between drug and the vehicle. The drug with the lowest p-value will be selected.Four weeks after TURBT, this selected drug will be used for intravesical instillation. Based on the results of the drug screen in PDO, patients will receive one of either (Epirubicin intravesical (50 mg/50 ml), Mitomycin C intravesical (40 mg/50 ml), Gemcitabine intravesical (1000 ml/50 ml) or Docetaxel intravesical (37.5 mg/50 ml)) once weekly for 6 weeks. | PMC10176900 | ||
Follow-up and data collection | CRF | CRF | The patients will be followed by cystoscopy according to the clinical guidelines [The CRF will be electronic. All data requested on the eCRF must be recorded and the recorded data should be consistent with the source documents or the discrepancies should be explained. The Investigator ensures the accuracy, completeness, and timeliness of the data reported in the eCRF and all other required reports. Generally, the eCRF should be completed within one week of completion of a participant’s visit/ follow-up phone call.The CRFs in this trial are implemented electronically using a dedicated electronic data capturing (EDC) system (REDCap ®, web-address: redcap.ctu.unibe.ch). The EDC system is activated for the trial only after successfully passing a formal test procedure. All data entered in the eCRF are stored on a Linux server in a dedicated Oracle database. | PMC10176900 |
Statistical methods for primary and secondary outcomes | REGRESSION, SECONDARY | The predictive potential of biomarkers for the primary and secondary outcome will be analysed using logistic regression.Missing data is expected to occur due to drop-outs. The amount and reason of missing data will be reported for all outcomes. For survival outcomes drop-outs will be censored at the time of the drop-out. | PMC10176900 | |
Data monitoring | For quality control of the study conduct and data retrieval, monitoring will be performed according to a monitoring plan determined by the Clinical Trial Unit from the University of Bern. Any findings and comments will be documented in site visit reports and communicated to the Sponsor-Investigator as applicable. Site staff will support the Monitor in his/ her activities. All source data and relevant documents will be accessible to Monitors and questions of Monitors are answered during site visits. All involved parties will keep participant data strictly confidential. | PMC10176900 | ||
Discussion | fits, cancer, NMIBC | CANCER, RECURRENCE | The major clinical challenges in NMIBC are the high rate of recurrence and the lack of a more precise delivery of care. Despite the molecular heterogeneity of NMIBC, all patients are treated according to the same protocol and followed by invasive and potentially harmful procedures.Therefore, we aim to precise the treatment of NMIBC thus making the therapy more effective.We believe that a more precise adjuvant treatment of NMIBC patients will reduce the risk of cancer recurrence and that drug screens in PDO may be a promising strategy to precise drug selection for intravesical instillation. The establishment of our protocols as part of clinical trials will allow us to investigate novel compounds for the intravesical treatment of NMIBC patients. Our in-vitro experiments may suggest other compounds for intravesical instillation that have not yet been investigated. In the future, we aim to conduct clinical multicenter trials with an increased sample size, a broader panel of compounds and a focus on the reduction of cancer recurrence by precision delivery of care.NMIBC is the costliest cancer on a per patient treatment basis. All patients are treated in a “one size fits all” manner and the workup at diagnostics and during follow-up is invasive and may be harmful. The success of this project will help to precise the treatment of patients with intermediate-risk NMIBC. Further, the establishment of our pipeline, will allow an effective and biologically driven investigation of novel compounds for intravesical instillation therapies. | PMC10176900 |
Acknowledgements | None | PMC10176900 | ||
Name and contact information for the trial sponsor | Spitalzentrum Biel, 2501 Biel, Switzerland. Represented by: Prof. Dr. med. Roland Seiler, Chairman. Department of Urology, Spitalzentrum Biel. Vogelsang 84, 2501 Biel, Switzerland. Email: Roland.Seiler-Blarer@szb-chb.ch | PMC10176900 | ||
Role of sponsor | The sponsor does not have a role in study design, collection, management, and decision to submit the report for publication. The sponsor provides the facility for the clinical work during this trial. | PMC10176900 | ||
Composition of the coordinating center and trial steering committee | Since this is a single center trial, coordinating center and trial steering committee are identical. It composes of Sponsor, Administrative study personal from the Department of Urology at the Hospital Center Biel and the Head of the group from the Translational Organoid CORE (TOR), University of Bern. Department for BioMedical Research (DBMR). Meetings will be held on a monthly basis. | PMC10176900 | ||
Composition of the data monitoring committee, its role and reporting structure | For quality control of the study conduct and data retrieval, monitoring will be performed according to a separate monitoring plan. Any findings and comments will be documented in site visit reports and communicated to the Sponsor-Investigator as applicable. Site staff will support the Monitor in his/ her activities. All source data and relevant documents will be accessible to Monitors and questions of Monitors are answered during site visits. All involved parties will keep participant data strictly confidential. | PMC10176900 | ||
Access to data | The trial protocol will be published in an open access journal. Study results will be presented at national and international meetings and will be submitted for publication to high impact, peer reviewed journals. Upon completion of the analysis, trial results will be communicated to all participants. Public reporting will be done through patient organizations and via the communication Departments of Spitalzentrum Biel. Once results have been published, trial data will be accessible to external researchers and anonymized datasets corresponding to each publication will be made available. Investigators wishing to replicate the analyses or to do an individual patient meta-analysis may request the data from the Sponsor-Investigator. Access to data will be granted in an unbureaucratic way. | PMC10176900 | ||
Dissemination plans | The trial protocol will be published in an open access journal. Study results will be presented at national and international meetings and will be submitted for publication to high impact, peer reviewed journals. Upon completion of the analysis, trial results will be communicated to all participants. Public reporting will be done through patient organizations and via the communication Departments of Spitalzentrum Biel. Once results have been published, trial data will be accessible to external researchers and anonymized datasets corresponding to each publication will be made available. Investigators wishing to replicate the analyses or to do an individual patient meta-analysis may request the data from the Sponsor-Investigator. Access to data will be granted in an unbureaucratic way. | PMC10176900 | ||
Confidentiality | The Investigator will maintain appropriate medical and research records for this trial, in compliance with ICH-GCP and regulatory and institutional requirements for the protection of confidentiality of subjects. The Principal Investigator, Sub-investigators, and Clinical Research Nurses or Coordinators will have access to the records. The Principal Investigator will permit authorized representatives of the Sponsor and regulatory agencies to examine clinical records for the purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. The Investigator ensures anonymity of the participants; participants will not be identified by names in any documents leaving the study site. Subject confidentiality will be ensured by utilizing subject identification codes and the subject code list will be maintained and kept locked under the responsibility of the Principal Investigator. Access to uncoded data including the code list will be restricted to members of the study team and will be allowed for the purposes of monitoring, audits, and inspections and, if required, for representatives of the responsible insurance company in a liability case. It will be kept in locked cupboards at the department of Urology of the Spitalzentrum Biel. | PMC10176900 | ||
Author contributions | RS, MR, MM, MDM | RS: conception, design and draft of the work. ME: Acquisition and interpretation of data. MDM: Conception and design of the work, acquisition and interpretation of data. MM: Acquisition and interpretation of data. MR: Acquisition and interpretation of data. SW: Data acquisition, protocol revision. PL: Conception, design and draft of the work. RH: Conception, design and draft of the work. JB: Conception and design of the work, protocol revision. DA: Conception and design of the work, protocol revision. MKJ: Conception, design and draft of the work. All authors read and approved the final manuscript. | PMC10176900 | |
Funding | Jetty, Aron und Simon Blum-Foundation and SNSF 310030_184933/1. | PMC10176900 | ||
Availability of data and materials | The trial sponsor will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators. | PMC10176900 | ||
Declarations | PMC10176900 | |||
Consent for publication | Not applicable. | PMC10176900 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10176900 | ||
References | PMC10176900 | |||
Background | Supplementation of calcium during continuous venovenous hemofiltration (CVVH) with citrate anticoagulation is usually titrated using a target blood ionized calcium concentration. Plasma calcium concentrations may be normal despite substantial calcium loss, by mobilization of calcium from the skeleton. Aim of our study is to develop an equation to calculate CVVH calcium and to retrospectively calculate CVVH calcium balance in a cohort of ICU-patients. | PMC10227114 | ||
Methods | This is a single-center retrospective observational cohort study. In a subcohort of patients, all calcium excretion measurements in patients treated with citrate CVVH were randomly divided into a development set ( | PMC10227114 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.