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Strategies to improve adherence to interventions {11c} | Using a commercially available feedback device ( | PMC10413586 |
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Relevant concomitant care permitted or prohibited during the trial {11d} | During the trial, NHSBT standard care has been in place to ensure donor safety. This includes a screening procedure to ensure the donor is healthy and any medication does not impact donor health or the donation process (including study interventions). As noted above, if a donor has declined to receive the trial intervention, they have been offered standard care. | PMC10413586 |
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Provisions for post-trial care {30} | Given its interventions, this trial is considered minimal risk; no specific post-trial care has, therefore, been provided. | PMC10413586 |
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Outcomes {12} | PMC10413586 |
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Primary outcome | loss of consciousness | COMPLICATIONS | The primary outcome is the number of in-session VVRs with loss of consciousness (i.e. episodes involving loss of consciousness of any duration, with or without additional complications). | PMC10413586 |
Secondary outcomes | bruising, loss of consciousness, rebleeds, non-VVR adverse | ADVERSE EVENTS, EVENT, APPENDIX, SECONDARY | Secondary outcomes are (i) all in-session VVRs (i.e. with and without loss of consciousness); (ii) all delayed VVRs (i.e. VVRs with and without loss of consciousness after leaving the donation venue); (iii) delayed VVRs with loss of consciousness; and (iv) any in-session non-VVR adverse events or reactions, such as bruising and rebleeds.All outcomes will be assessed at the end of the trial and will involve comparison of event rates in periods with and without interventions applied (Appendix 1). The data on the primary and secondary outcomes will be complete by design, as the recording of on-session adverse events, including VVRs, is mandatory in the blood service. | PMC10413586 |
Participant timeline {13} | All donors who have attended a blood donation session from 4 | PMC10413586 |
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Sample size {14} | syncope | The trial sample size has been informed by (i) the need to generate evidence sufficiently compelling to influence regulators and policy-makers; (ii) NHSBT's duty of care to 900,000 blood donors per year, making it vital for the service to evaluate even small changes in VVR rates; (iii) NHSBT’s objective to optimise blood collection procedures, improve donor return rates, and improve donor (and staff) well-being and satisfaction; and (iv) the need for appropriate power to study determinants of VVRs, both singly and in combination.Power calculations have been based on the primary endpoint (defined above), assuming a 5% type I error probability and service-wide cluster randomisation (involving 73 teams with ~15,000 whole blood donations per 9-month period per team, and overall primary outcome rate of 0.18% per donation). For the two interventions being assessed using a cross-over design (i.e. isotonic drink and time on donation chair after donation), there is >90% power to detect an odds reduction of >8% (odds ratio of 0.92). For the two interventions being assessed using a stepped-wedge design (i.e. modified AMT and psychosocial intervention), there is >90% power to detect an odds reduction of >13% (odds ratio of 0.87) (Fig. Statistical power of the trial. Calculated for the two interventions in the study were assessed using a cross-over design (i.e. isotonic hydration and time on donation chair after donation; red line) and the two interventions in the study were assessed using a stepped-wedge design (i.e. modified AMT (applied muscle tension) and psychosocial intervention; blue line). Each intervention was tested at a Bonferroni corrected level (type I error) of 0.0125. The study design has four possible sequences for interventions assessed using a stepped-wedge design (X-I-I-I, X-X-I-I, X-X-X-I, X-X-X-X), and two possible sequences for interventions assessed using a cross-over design (X-I-X-I, I-X-I-X) with a study duration of 3 years and each period lasting 9 months (X = current practice, I = intervention). Power calculations assume 15,000 whole blood donations per 9-month period in each donation centre, with an overall rate of severe (syncope) VVRs of 0.18% per donation and a between-centre variance in log odds of 0.06 (estimated from 2014/15 NHSBT data) | PMC10413586 |
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Recruitment {15} | All individuals who have donated blood in one of NHSBT’s blood donation sessions during the trial period have been included in the trial, unless they opted out using the procedure described above. | PMC10413586 |
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Assignment of interventions: allocation | PMC10413586 |
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Sequence generation {16a} | Randomisation of donation sites (“clusters”) to intervention sequences has been undertaken at the trial’s academic coordinating centre, using a computer program written to implement a previously described method for sequential treatment assignment, balancing for known prognostic factors [ | PMC10413586 |
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Concealment mechanism {16b} | During the study period, only two people (the trial statistician and study coordinator) were aware of the study randomisation. NHSBT teams (clusters) were informed of the upcoming intervention changes approximately 1 week prior to commencement to allow them to order supplies to deliver the interventions. This process was repeated for each 9-month period. | PMC10413586 |
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Implementation {16c} | The trial statistician at the academic coordinating centre generated the allocation sequence at the beginning of the trial. Every 9 months, when the intervention allocations changed, the trial statistician contacted staff at NHSBT to roll out the next phase of interventions. | PMC10413586 |
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Assignment of interventions: blinding | PMC10413586 |
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Who will be blinded {17a} | As noted above, participants and analysts have not been blinded to the interventions they have received. | PMC10413586 |
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Procedure for unblinding if needed {17b} | Not applicable, this trial is not blinded. | PMC10413586 |
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Data collection and management | PMC10413586 |
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Plans for assessment and collection of outcomes {18a} | SFTP | ADVERSE EVENTS, EVENTS | Via a Secure File Transfer Protocol (SFTP), NHSBT staff have shared pseudonymised information about donors’ demographic characteristics and adverse donation events (including VVRs) with authorised staff at the academic coordinating centre. All data shared have been strictly pseudonymised (i.e. stripped of personal identifiers). To enhance collection of information on relevant trial outcomes, NHSBT staff have sent donors SMS text messages immediately after donation visits, asking them to report any adverse events by phoning the NHSBT Customer Care line. All adverse events reported by the donors will be assessed by a nurse at the time of reporting and if considered serious, the coordinating centre is informed, along with the study Sponsor and ethics committee. | PMC10413586 |
Plans to promote participant retention and complete follow-up {18b} | Not applicable; this trial does not involve the need for participant retention or follow-up beyond the mechanisms described above. | PMC10413586 |
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Data management {19} | SFTP | ADVERSE EVENTS | A formal Data Sharing Agreement was agreed between NHSBT and the University of Cambridge, prior to the start of the STRIDES trial. On a daily basis, NHSBT staff have forwarded to an authorised data manager at the academic coordinating centre pseudonymised extracts from NHSBT’s database including information on donors: donation history, attendance and deferrals; adverse events; microbiology results; merged donor records; and the right to be forgotten. Reports have been in .csv format (accessible only to authorised staff) and uploaded to the SFTP site. These daily extracts have been imported into a password-protected restricted access SAS database where the provided anonymous ID (GUID) has been replaced by a separate anonymous study ID; the link table between GUID and study ID has been available only to an authorised data manager at the academic coordinating centre.Queries are automatically generated by the STRIDES Data Management systems (written in SAS) by cross-checking/looking for inconsistencies in the data. Resulting queries are resolved by the study helpdesk, by either looking things up in NHSBT systems or contacting the participant directly. Once resolved, any updates/corrections are entered into an Access database by the helpdesk. The Access database is then automatically read into the Data Management systems and updates corrections are automatically implemented. The Data Management Team is responsible to review the data and ensure it is clean prior to analyses. | PMC10413586 |
Plans to give access to the full protocol, participant-level data and statistical code {31c} | Data access requests should be made to [email protected]. | PMC10413586 |
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Confidentiality {27} | Not applicable; no personal, identifiable information is collected as part of this trial. | PMC10413586 |
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Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} | SECONDARY | During the trial period, a subset of donors have been asked if they wish to join the STRIDES/NIHR BioResource – Research Tissue Bank (henceforth, ‘STRIDES BioResource’), in keeping with the trial’s secondary objective to advance understanding of the determinants of VVRs and to help develop prevention strategies for VVRs tailored to specific donor sub-populations, based on demographic, biological, psychosocial, and other characteristics. Donors who consent to participate in the STRIDES BioResource have been asked to provide a 20-ml blood sample (at the session) and to complete online questionnaires (after the session) concerning VVRs and broader health and donation questions. A full blood count has been performed from the collected blood sample using a Sysmex-XN haematology analyser (Sysmex UK Limited, Milton Keynes, UK) to generate an extended profile of blood cell indices. Full blood count results were reviewed by NHSBT staff to identify clinically significant results for further consideration. As the STRIDES BioResource is part of the NIHR BioResource, consenting donors have also joined the NIHR BioResource Research Tissue Bank (REC: 17/EE/0025) ( | PMC10413586 |
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Statistical methods | PMC10413586 |
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Statistical methods for primary and secondary outcomes {20a} | PMC10413586 |
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Principles | Intention-to-treat analyses will be used. Principal analyses will concern the assessment of the main effects of interventions based on outcomes aggregated at the site level (i.e. unit of randomisation). Tests of interaction will assess whether results differ between pre-specified subgroups. Subsidiary analyses will be done using individual-level data with allowance for clustering of observations by site. Multiple testing will be taken into account when interpreting results other than the principal analyses. The trial will be reported according to CONSORT guidelines. | PMC10413586 |
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End-of-trial analyses | SECONDARY | Primary analyses will calculate odds ratios for the main effects of interventions using a binomial generalised linear mixed model fitted to the aggregate number of primary outcomes recorded in each 9-month period by site with the denominator as the number of donations recorded by site-period (defined by NHSBT as a complete donation or a partial donation). Adjustments will be made for the baseline prognostic variables considered for balancing at randomisation (i.e. historical VVR rates, total numbers of donors bled, and type of site), plus dummy variables for the four nine-month periods of intervention, and a random effect for the site. Key secondary analyses related to the primary outcome will include an assessment of interactions of interventions and possible variation of the main effects by period and baseline characteristics. Analyses of other secondary outcomes will follow the same approach as for the primary outcome. | PMC10413586 |
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Interim analyses {21b} | Not applicable; interim analyses have not taken place as the trial has been judged to be minimal risk. | PMC10413586 |
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Methods for additional analyses (e.g. subgroup analyses) {20b} | Key additional analyses will include an assessment of interactions of interventions and possible variation of the intervention main effects by period and site-level baseline characteristics, including faint rates (tertiles); size as characterised by a number of donors bled (tertiles); and type of site (fixed or mobile). Analyses will follow the same approach as for the primary outcome with the addition of relevant interaction terms. Furthermore, individual-participant data will be secondarily analysed using a hierarchical generalised linear mixed model to assess possible interactions of interventions with selected participant characteristics (e.g. age, sex) accounting for the cluster randomised trial design at the site level. | PMC10413586 |
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Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} | As noted above, all analyses will involve the intention to treat principle. Data on outcomes and covariates are expected to be mostly complete as they are anonymously collected from routine blood donation records, with low opt-out rates for use in consented research. We will report on any missing data, but will not conduct data imputation. | PMC10413586 |
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Oversight and monitoring | PMC10413586 |
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Composition of the coordinating centre and trial steering committee {5d} | The Trial Steering Committee monitors the overall conduct of the trial and, through its independent Chair, provides strategic advice to the Trial Management Group. The Trial Steering Committee includes several senior clinical and academic members who are independent from the trial investigators, two lay representatives, and representatives of various stakeholders in STRIDES and meets approximately two to three times per year. Furthermore, the Trial Management Group (which includes the investigators, trial coordinators, members of the PPIE panel, and operational staff from NHSBT) is responsible for overseeing the day-to-day management of the study, liaising with NHSBT, and agreeing protocol amendments prior to submission to the research ethics committee. This Management Group meets monthly throughout the study period. | PMC10413586 |
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Composition of the data monitoring committee, its role and reporting structure {21a} | RECRUITMENT | An independent data monitoring committee was not set up for this study. The main reason for this is the study is minimal risk to human health. The Trial statistician has analysed information on recruitment, baseline characteristics, and total counts of all VVRs recorded approximately two times per year, and presented summary data to the Trial Steering Committee, which then makes the decision on whether the study should continue. | PMC10413586 |
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Patient and public involvement and engagement | Within the department, there is a well-established panel of public contributors who are current or past blood donors. Two members of the public (blood donors) joined the STRIDES trial management group (TMG) during the design phase and a third member of the public joined six months before the start of the feasibility study. Public members were involved in study design, development of study materials, implementation, governance and decision-making about dissemination of study outcomes. Two additional blood donors sat on two other overarching governance and steering committees. Feedback was also collected from blood donors on the study documentation including patient information leaflet, study consent form, communication text (SMS, website), and design of the interventions (e.g. selecting isotonic drink brand/flavours).Forms of dissemination will include academic publications, conference presentations, stakeholder meetings, and workshops with blood donors. For the public and other relevant stakeholders, the trial protocol and results will be disseminated via website, email and social media. We will also prepare materials to share key information with NHSBT staff, blood donors and the general public. Lay materials will be co-designed with blood donors and NHSBT, to ensure they are relevant, understandable and impactful. | PMC10413586 |
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Adverse event reporting and harms {22} | ADVERSE EVENTS, ADVERSE EVENT | Any serious adverse events that occurred during or immediately after the study period will be reported to the Research Ethics Committee and NHSBT by email ([email protected]) within 24 h days, according to the Health Research Authority guidelines. Adverse events that are not serious are recorded and the sponsor of the study is informed within 15 days. | PMC10413586 |
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Frequency and plans for auditing trial conduct {23} | As noted above, during the trial period, each blood donation team within NHSBT has been audited at least once during each intervention period (i.e. every 9 months). During these visits, NHSBT staff members recorded what interventions were in place at the team they visit along with any other relevant observations. The study group then reviewed these findings and identified any potential discrepancies. If any discrepancies appeared, the site has been asked to amend their practices in line with the study protocol. | PMC10413586 |
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Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} | Study amendments, following approval from the Research Ethics Committee and the Sponsor, have been communicated to NHSBT blood donation teams via email. If additional training has been needed, virtual training sessions have been set up to ensure the amendment has been understood and implemented. | PMC10413586 |
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Dissemination plans {31a} | Results from this study will directly inform NHSBT’s blood donation policies. The results will also be published in relevant journals and presented at conferences across the world. Our PPIE members will also be involved in the dissemination of results through our Trial Steering Committee and TMG. | PMC10413586 |
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Discussion | To our knowledge, STRIDES is the largest and most comprehensive cluster randomised trial to date in the prevention of VVR among whole blood donors. The rationale for its conduct was suggested by our prior systematic review and meta-analysis of previous randomised trials assessing the effects of water loading, AMT and other interventions, which highlighted serious limitations in the quality and quantity of available randomised evidence [We anticipate that the STRIDES trial will yield novel information about the four pragmatic and scalable interventions we are assessing, both singly and in combination, for the prevention of VVRs. The trial results should, therefore, help generate policy-shaping evidence to inform blood services to improve donor health, donor experience, and service efficiency.More generally, this trial exemplifies another instance of NHSBT’s continuing aspiration, in collaboration with strategic academic partners, to be a “learning health organisation” in which internal data and experience are systematically integrated with external evidence, and that knowledge is put into practice to improve safety and efficiency in NHSBT and, potentially, in other blood services [ | PMC10413586 |
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Trial status | RECRUITMENT | Recruitment to the STRIDES study began in November 2019 and will complete in November 2022. Currently protocol version v4.0, 13.07.2020 | PMC10413586 |
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Acknowledgements | Turner and Laura Wood, Hunt/Lydia, Alison Dent / Claudia, Sutton Coldfield | SLOUGH, WRIGHT, STUART, BRAIN, DAWSON, WELLS, ROBINSON, HEART, GROVER, GILCHRIST | This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care
(England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome.Independent Chair and Clinical Trialist (Prof Jane Armitage); Funders (Dr Gail Miflin, Jane Green, Mike Stredder, Prof David Roberts, Dr Farrah Shah); Chief and Principal Investigators (Prof Emanuele Di Angelantonio, Prof John Danesh); Sponsor Representative (Dr Nick Watkins and Oluwayomi Adegbaju) Scientific Coordinator (Dr Amy McMahon); NHSBT Consultant Haemotologist (Prof Mike Murphy) NBR Laboratory Coordinator (Dr Jennifer Sambrook, Dr Kathy Stirrups); Senior Statisticians (Dr Angela Wood, Dr Stephen Kaptoge); Chief Information Officer (Dr Matthew Walker); NHSBT Project Lead (Susan Mehenny), Project Administration/coordination (Susan Burton, Shannon Duthie, Elisha Johnson); NIHR BioResource Representative (Dr Nathalie Kingston), Independent Member (Prof Beverley Hunt,) and Lay Members (Ms Elizabeth Morse and Ms Roxanne Stirling).
Principal and co-Investigators (Prof Emanuele Di Angelantonio, Prof John Danesh, Prof David Roberts and Dr Philippe Gilchrist); Scientific Coordinator ( Dr Amy McMahon); Sponsor Representative (Dr Nick Watkins and Oluwayomi Adegbaju), NBR Representative (Dr Nathalie Kingston), NBR Laboratory Coordinator (Dr Jennifer Sambrook, Dr Kathy Stirrups); Chief Information Officer (Dr Matthew Walker); NBR Informatics Director (Dr Neil Walker) Senior Statisticians (Dr Stephen Kaptoge, Dr Angela Wood, Dr Michael Sweeting); NHSBT Project Lead (Susan Mehenny); Senior Research Sister North (Rosemary Godfrey); Senior Research sister South (Louise Allen); Project Administration NHSBT (Joanne Addy, Louise Stennett); Project Administration/coordination, University of Cambridge (Elisha Johnson, Shannon Duthie, Susan Burton, Susan Irvine); NHSBT Consultant (Naim Akhtar); Lay Members (Paul Harvey, Elizabeth Allen and Michael Berkson)
Katherine Willdridge (Ashford), Matt Byron (Bath), Anna Turco (Beckenham Team), Richard Brain (Birmingham Donor Centre), Ruth Turner and Laura Wood (Bradford Donor Centre), Clare Carman (Brighton), Charlotte Hughes and Rachel Newman (Bristol), Alison Dent / Claudia Hana (Bristol Donor Centre), Kennesha McIntosh (Cambridge), Alan Wakeman (Cambridge Donor Centre), Ana Corexo (City), Mandy Wright (Cornwall), Fiona Price (Coventry), Sharon Donald (Cumbria), Louise Easton (Dorchester), Nicole Ciulea (Edgware Donor Centre), Vanessa Hunt/Lydia Bullard (Essex Team), Michaela Clarke (Exeter), Ruth Aston (Gloucester Donor Centre), Natalie Peters (Herts), Anna Turco (Hither Green), Clare Carman (Horsham), Susan Baker (Hull), Karen Wright (Huntingdon), Danielle Redden (Ipswich), Barbara Manhambara (Lancaster), Rachel Adams / Georgina Belvins (Lancaster Donor Centre), Marc Hudson (Leeds), Lynne Ainsworth (Leeds City Donor Centre), Adele Mayer (Leicester), Karen Ellis (Leicester Donor Centre), Victoria East (Lincoln), Sharon Jones (Liverpool), Theresa Robinson (Liverpool Donor Centre), Claire Anthony (London Middlesex), Emma Martin (Luton Donor Centre), Grace De Lira (Maidstone), Sue Platt / Karen Ackerley (Manchester), Lindsay Williams (Manchester Norfolk House), Karen Ackerley & Jo Holbrook (Manchester Plymouth Grove), Christina Hackney (Milton Keynes), John Townsend (Newcastle), Lynn Woods and Maria Dineen (Newcastle Donor Centre), Kate Fulton (Northampton), Ruth Patterson (Northwich), Amanda Rock (Norwich), Lorraine Pick (Nottingham), Jenny Wright (Nottingham Donor Centre), Kakale Sebogiso (Oxford Donor Centre), Caroline Morrice (Plymouth Donor Centre), Vicky Roberts (Poole Donor Centre), Judy McCabe (Portsmouth), Penny Crook-Jones (Reading), Jane Dawson (Sheffield Donor Centre), Catherine Fretwell (Sheffield North), Jill Rowlands / Penny Swift (Sheffield South), Sam Clark (Slough), Simone De-leon (Solihull ), Claire Alexander (Southampton Donor Centre), Annie Butterworth & Dona Blofield (Southampton Team), Diane Furnival (Stoke Donor Centre), Chanelle Henry (Surrey), Adele Lapworth / Clare Bloomfield (Sutton Coldfield), Penny Crook-Jones (Swindon), Sally Bleeks (Taunton), Jennifer O’Brien & Alison Thomson (Teesside), Patsy Lowson (Thetford), Christine St Romaine (Tooting Donor Centre), Karl Grover (Tunbridge Wells), Carolyn Roost / Sasa Cromack (WEDC), Rebecca Guest (Worcester), Tracy Bell (York)
Joanne Addy, Patricia Barrass, Louise Stennett.
Shannon Duthie, Elisha Johnson. Previous members: Susan Irvine, Rachel Henry, Susan Burton, Mercedesz Juhasz.
Matthew R Walker, University of Cambridge; Charlotte Van Coeverden, University of Cambridge; Michael Daynes, NHSBT, Stuart Halson, NHSBT
Stephen Kaptoge, University of Cambridge; Michael Sweeting PhD, University of Leicester, Angela Wood, University of Cambridge, Ryan Chung, University of Cambridge. | PMC10413586 |
Authors’ contributions {31b} | SD | EDA and JD are the chief investigators. AM, SK, MW, PTG, NW, NK, NA, JRB, GM and DJR are co-investigators. SK is the chief statistician. MS, AMW and RC are trial statisticians. MW is the chief data manager. SM, DC, RG and LA led the study within NHSBT. JS and KS managed the samples collected. SF managed the PPIE input for the trial. AM, EJ and SD coordinated the study and managed the study helpdesk. PH, MB and EA are PPIE members. JA is the independent chair of the Steering Committee. AM, SK, MW and EDA wrote the initial draft of the paper. All members of the writing committee have contributed to the conception, design, and execution of the trial, All co-authors have provided comments on the manuscript and have read and approved the submitted version of this manuscript. | PMC10413586 |
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Funding {4} | ’ S.K. | BLOOD, HEART | The trial is funded by NHS Blood and Transplant and the NIHR Blood and Transplant Research Unit in Donor Health and Behaviour (NIHR203337) (formerly Donor Health and Genomics; NIHR BTRU-2014–10024) and NHS Blood & Transplant (17-01-GEN). The academic coordinating centre at the Department of Public Health and Primary Care at the University of Cambridge receives core support from the British Heart Foundation (RG/13/13/30194; RG/18/13/33946) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). We thank NIHR BioResource volunteers for their participation and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care [*]. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the STRIDES trial. *The views expressed are those of the author(s) and not necessarily those of the NIHR, NHSBT or the Department of Health and Social Care.Persons from the University of Cambridge academic coordinating centre were funded by the NIHR Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics (NIHR BTRU-2014–10024) and are now funded by the NIHR BTRU in Donor Health and Behaviour (NIHR203337) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312) [*].’ S.K. is funded by a BHF Chair award (CH/12/2/29428). R.C. is funded by a BHF PhD studentship (FS/18/56/34177). A.M.W. is part of the BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No 116074 and is supported by the BHF-Turing Cardiovascular Data Science Award (BCDSA\100005). J.D. holds a British Heart Foundation Professorship and a NIHR Senior Investigator Award [*]. M.R.W. is funded by a BHF Chair award (CH/12/2/29428). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. | PMC10413586 |
Availability of data and materials {29} | Data access requests should be sent to [email protected] | PMC10413586 |
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Declarations | PMC10413586 |
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Ethics approval and consent to participate {24} | This study was approved by Cambridge South Research Ethics Committee (REC reference: 18/EE/0284). | PMC10413586 |
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Consent for publication {32} | Participants provided consent for the publication of anonymous summary data. | PMC10413586 |
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Competing interests {28} | J.D. serves on scientific advisory boards for AstraZeneca, Novartis, and UK Biobank, and has received multiple grants from academic, charitable and industry sources outside of the submitted work. M.S. is a full-time employee of AstraZeneca. | PMC10413586 |
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References | PMC10413586 |
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Background | neurotoxicity, gastro-esophageal adenocarcinoma | Paclitaxel in combination with ramucirumab is the standard of care second-line therapy in gastro-esophageal adenocarcinoma (GEA). As the number of taxane pretreated patients in the perioperative or first-line setting is increasing, it is unknown whether these patients benefit from re-applying a taxane in using the combination of paclitaxel and ramucirumab. Furthermore, the rates of neurotoxicity with first-line FOLFOX or FLOT range from 30%–70%, making second-line taxane‐containing therapy less suitable to a meaningful portion of patients. This patient group is likely to benefit from a taxane-free second-line chemotherapy regimen, such as FOLFIRI and ramucirumab (FOLFIRI-Ram). Therefore, the RAMIRIS phase III trial evaluates the effects of the regimen of FOLFIRI-Ram in the second-line treatment after a taxane-based chemotherapy in patients with advanced GEA. | PMC10278289 |
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Methods | The RAMIRIS trial is a randomized, open-label, multicenter phase II/III study comparing treatment of FOLFIRI-Ram (arm A) with paclitaxel and ramucirumab (arm B). The Phase II is already closed with 111 enrolled patients. In the phase III, 318 taxane-pretreated patients with advanced GEA will be recruited and randomized 1:1 to FOLFIRI (5-FU 2400 mg/m | PMC10278289 |
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Discussion | toxicity | The already completed RAMIRIS phase II demonstrated feasibility and efficacy of FOLFIRI-Ram. Especially docetaxel-pretreated patients seemed to markedly benefit from FOLFIRI-Ram, with favorable response- and PFS rates and lower toxicity. This offers a rationale for the phase III trial. If the RAMIRIS III trial transfers and confirms the results, they will affect the current treatment guidelines, recommending the combination therapy of FOLFIRI-Ram for taxane-pretreated patients with advanced GEA. | PMC10278289 |
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Trial registration | NCT03081143 | NCT03081143 Date of registration: 13.11.2015 | PMC10278289 |
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Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10278289 |
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Background | colorectal cancer, toxicity, cancer, cancer death, adenocarcinoma, deaths | CANCER, COLORECTAL CANCER, ADENOCARCINOMA, DISEASE PROGRESSION | Gastro-esophageal adenocarcinoma (GEA) is the fifth most common cancer worldwide, causing over one million new cases (1,033,701) each year and is the third-leading cause of cancer death (about 782,685 deaths and 8.2% of total in 2018) [At initial diagnosis more than two thirds of patients are not suitable for curative treatment, because they have an advanced stage GEA [In the long-term, nearly all patients fail to first line-line therapy and suffer from disease progression. Only 42%-54% of those patients receive another treatment regimen [Ramucirumab is an accepted second line therapy in advanced GEA either as monotherapy or in combination with paclitaxel [In the second-line setting Irinotecan as a monotherapy or in combination with 5-FU/Folinic Acid (FOLFIRI) is a safe and efficient regimen and has shown a significant improvement of OS compared to BSC for patients with progressive GEA [With regards to toxicity, additional support for the safety and efficacy of FOLFIRI in combination with ramucirumab (FOLFIRI‐Ram) was established in the RAISE trial in second-line advanced colorectal cancer after progression on 5-FU/Folinic acid and Oxaliplatin (FOLFOX) with bevacizumab [ | PMC10278289 |
Study rationale | NCT03081143, neurotoxic | RECURRENCE | Current treatment algorithms recommend a taxane- containing triplet regimen for selected patients as first-line therapy for advanced GEA [Recurrence rates for initially curative treated patients remain high, ranging between 36% to about 70% for patients who received a taxane containing perioperative regimen [As a significant number of patients with GEA suffer from neurotoxic side-effects after first-line treatment with FOLFOX (30–70%) a second line treatment containing a taxane is less reasonable for this group [The safety analysis of the phase II RAMIRIS trial did not reveal any unexpected safety issues. The results of the safety interim analysis provide further support for the safety and efficacy of second-line FOLFIRI-Ram in this patient group [Therefore, the Arbeitsgemeinschaft Internistische Onkologie (AIO) investigators implemented a phase III portion of the RAMIRIS phase II trial, which is currently ongoing (NCT03081143). The phase III portion will not utilize the patients enrolled into the phase II portion.The phase III portion of the RAMIRIS trial will evaluate whether the combination of FOLFIRI-Ram (investigational arm A) is superior in terms of OS and ORR compared to the standard treatment of ramucirumab plus paclitaxel (control arm B) in patients who had received a taxane (docetaxel or paclitaxel). This might lead to a new standard of care in this particular group of patients by changing the national and international guidelines. | PMC10278289 |
Methods / Design | ADVERSE EVENTS, DISEASE | The RAMIRIS trial is a randomized, open-label, multicenter phase II/III study comparing treatment of FOLFIRI-Ram (arm A) with paclitaxel and ramucirumab (arm B) in patients with GEA after prior taxane containing therapy. The study will evaluate the safety and efficacy of the treatment regimens including quality of life.A total number of 318 patients will be recruited, from which 159 patients will be randomized in arm A (FOLFIRI-Ram) and 159 will be treated with paclitaxel and ramucirumab (arm B) (Fig. Study design of the RAMIRIS Phase III TrialThe protocol has been approved by the individual institutional ethics committees. All patients provided written informed consent prior to study participation.The primary endpoint of the phase III trial is to compare OS in patients with locally advanced and inoperable or metastatic GEA receiving FOLFIRI-Ram versus paclitaxel and ramucirumab as second-line therapy and who failed prior taxane-containing therapy in the intent to treat population (ITT).Secondary endpoints are to compare the disease control Rate and the PFS as well as the quality of life between the two treatment arms. The safety and tolerability of ramucirumab and FOLFIRI or paclitaxel are evaluated by monitoring the incidence, frequency and severity of adverse events (AE) according to NCI-CTCAE V 4.03 [ | PMC10278289 |
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Participants | therapyCapability, gastric adenocarcinoma | DISEASE PROGRESSION, RECURRENCE, LIVER METASTASES, ONCOLOGY, GASTRIC ADENOCARCINOMA | Eligible patients need to fulfill all of the following criteria:
Signed written informed consentWomen or men ≥ 18 years of age; Patients in reproductive age must be willing to use adequate contraception during the study and for 3 months after the end of ramucirumab treatment. Women of childbearing age need to have a negative pregnancy test within 7 days before study start. Patients will be enrolled gender-independently.Proven histology of gastric adenocarcinoma including adenocarcinoma of the esophagogastric junctionMetastatic or locally advanced, inoperable diseaseRadiological or clinical disease progression during or after the last dose of a first-line platinum, fluoropyrimidine-containing therapy. Patients must also have received a taxane with the first-line and/or during their adjuvant or neoadjuvant therapy in a curative setting. Neoadjuvant/adjuvant platinum containing therapy is permitted and is counted as first-line therapy if progression occurs within 12 months after completion of the treatment. The therapy is not considered as a treatment line, if progression or recurrence occurs 12 months after end of last treatment. In case of different prior treatments, they can be considered as one therapy line, if they were administrated as a continuous or alternating therapy.Measurable or non-measurable but evaluable diseaseEastern Cooperative Oncology Group Status must be less than or equal to 0–1Expectancy of life must be less than or equal to 12 weeksReasonable hematological, hepatic and renal functions:Absolute neutrophil count (ANC) ≥ 1.5 x 109/LPlatelets ≥ 100 x 109/LHemoglobin ≥9 g/dL (5.58 mmol/LTotal bilirubin ≤ 1.5 UNLAST (SGOT) and ALT (SGPT) ≤ 2.5 x UNL without liver metastases, or ≤ 5 x UNL in case of liver metastases; AP ≤ 5 x UNLSerum creatinine ≤ 1.5 x ULN, or creatinine clearance ≥40 mL/minuteUrinary protein ≤1+ on dipstick or routine urinalysis; if urine dipstick or routine urine analysis is ≥2+ of urinary protein, patients need a 24-hour urine collection and protein must be below <1000 mg in 24 hoursAn adequate coagulation function measured by the International Normalized Ratio ≤ 1.5 and the partial thromboplastin time ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be changed to low molecular weight heparin and need to show a stable coagulation profile before start of first dose of therapyCapability to follow scheduled assessments and to dope with side effects. | PMC10278289 |
Study treatments | PMC10278289 |
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Arm A - Experimental Treatment consists of: |
Ramucirumab 8 mg/kg intravenously on day 1, 15; q28FOLFIRI (intravenously: Irinotecan 180 mg/m | PMC10278289 |
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Arm B - Standard Treatment consists of: |
Ramucirumab 8 mg/kg intravenously on day 1, 15; q28Paclitaxel 80 mg/mEach cycle will be repeated after 28 days (from day 1) for a maximum of 1 year. | PMC10278289 |
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Assessment | tumor, Tumor | DISEASE PROGRESSION, TUMOR, METASTASES, TUMOR | Tumor assessment for study inclusion will be performed within 4 weeks prior to the first dose of study therapy and every eight weeks while treatment. The assessment will be performed by CT scan or MRI from chest to pelvis and all other sites of metastases and should continue until progression. Patients who discontinue trial therapy prior to disease progression should continue to have tumor assessments as per protocol schedule until progression. Tumor assessments are evaluated in accordance with to RECIST 1.1 [ | PMC10278289 |
Follow up | Tumor | DISEASE PROGRESSION, TUMOR | After discontinuation of study medication patients will be followed up for at least 1 year, every 2 months (except for the first follow up visit, which will be after 30 days due to safety reasons). Tumor assessments per CT scan or MRI will be performed every 8 weeks or until disease progression according to clinical routine. | PMC10278289 |
Statistical methods and data analysis | toxicity, death | EVENT, REMISSION, SOLID TUMORS | The intention of the RAMIRIS Phase III trial is to show a superior therapeutic efficacy of the experimental regimen FOLFIRI-Ram compared to the combination of paclitaxel and ramucirumab in patients pretreated with a taxane. Accordingly, the research hypothesis of the study is one-sided. The primary endpoints are OS and ORR according to RECIST. OS is defined as the time from randomization to death from any cause. Further the aim is to compare the ORR in the two groups. ORR is defined as the percentage of patients with complete or partial remission as their best overall response based on Response evaluation criteria in solid tumors 1.1. (RECIST) [A Bonferroni type adjustment of the α error level, due to multiple testing, will be applied. The OS and PFS will be estimated by using the Kaplan–Meier method and logrank test. Hazard ratios will be obtained from corresponding Cox proportional hazard models. ChiAll parameters (except for the co-primary endpoints) will be measured in an explorative or descriptive way. All p values will be two-sided if not explicitly mentioned (co- primary endpoints of phase III). The suitability of the methods will be reevaluated after the data has been received. If required, the statistical method will be adapted accordingly, with critical discussion.OS, ORR, rate of toxicity and other event rates are estimated at pre-defined time points, confidence intervals will be provided. For data analysis Fisher ´s exact test, chiNo formal interim analyses on efficacy or futility are planned for the phase III portion. | PMC10278289 |
Sample size estimation | Looking at results of the RadPAC Trial [On the other hand, only 298 patients are aquired to ensure 80% power to detect an improvement from 10 to 25% for the co-primary endpoint ORR based on an one-sided α error of 0.005. Therefore, 318 patients will be randomized. | PMC10278289 |
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Discussion | taxane-treated, neutropenia, fatigue, diarrhea, neurotoxicity | CPS, NEUTROPENIA | A high number of first-line taxane-treated patients with GEA relapse and require a second-line treatment. However, data is scarce, whether they benefit more from a re-exposure to a taxane-containing therapy, such as the standard regimen paclitaxel and ramucirumab, than from a taxane-free regimen. Therefore, the Phase III RAMIRIS trial will prospectively provide evidence on the safety and efficacy of second-line FOLFIRI‐Ram after progression on first-line platinum/5-FU in patients pretreated with a taxane.Clinical data shows, that second-line treatment with FOLFIRI-Ram is safe and shows no additional neurotoxicity. In the evaluation of the RAMIRIS phase II portion the feasibility of FOLFIRI-Ram could be confirmed: Grade 3 or higher AEs reported were mainly neutropenia (20% in die experimental group vs. 22% in the standard group), diarrhea (8% in die experimental group vs. 3% in the standard group fatigue) and.fatigue (6% in die experimental group, no fatigue was reported in the standard group). Serious treatment-related AEs were observed in 14% of patients in the experimental group and 23% of patients in the standard group [Studies show that the combination of FOLFIRI-Ram or Irinotecan and ramucirumab compares favorably to the standard regimen paclitaxel and ramucirumab [The study was designed and initiated in 2015. During this time, no patients with GEA were treated with immunotherapy as standard of care. Therefore, pre-treatment with immunotherapy was not explicitly mentioned in the eligibility criteria. Since immunotherapy is now standard of care for selected patients according to the CPS (combined positive score), patients pretreated with immunotherapy can be included. There are even signals from retrospective analysis that immunotherapy pretreated patients have an improved survival when subsequently treated with the combination of Ramucirumab plus chemotherapy versus chemotherapy alone due to a synergistic effect of immunotherapy and anti VEGF-receptor therapy [The outcomes of the retrospective study evaluating FOLFIRI-Ram as a second-line treatment for patients with GEA by Klempner et al. and the phase III trial investigating ramucirumab and irinotecan in third-line treatment or beyond for GEA patients by Sakai et al. resulted already in the inclusion of FOLFIRI-Ram or irinotecan-Ram in the NCCN Clinical Practice Guidelines as a second-line treatment for GEA [In summary published data strongly supports the rationale for expansion to phase III of the RAMIRIS trial. If the results can be confirmed they will affect the current treatment guidelines, recommending the combination therapy of FOLFIRI-Ram for taxane-pretreated patients with advanced GEA. | PMC10278289 |
Acknowledgements | We thank the patients and their families, the team at Lilly, namely Dr. Christian Schneider-Fresenius, the trial coordination team at the IKF, namely Dr. Claudia Pauligk and all the sites and study teams participating in the trial | PMC10278289 |
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Authors’ contributions | SL, CP, EG, GS, JRK, GI, TD, MM, JCM, DP, TOG, AS and SEA designed the clinical trial, developed the protocol and recruited patients. The statistics are done by MS. SL and AS wrote the manuscript. SL, CP, EG, GS, JRK, GI, TD, MM, JCM, DP, MS, TOG and SEA contributed to the development and finally approved the manuscript. The author(s) read and approved the final manuscript. | PMC10278289 |
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Funding | Open Access funding enabled and organized by Projekt DEAL. The legal sponsor of the trial is the Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest (Steinbacher Hohl 2–26, 60488 Frankfurt am Main, Germany). The trial is supported by a research grant for conduction of the clinical trial and supply of study medication (ramucirumab in Arm A) by Lilly Deutschland GmbH. Lilly did not influence the content of this trial. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. | PMC10278289 |
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Availability of data and materials | Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Steinbacher Hohl 2–26, 60,488 Frankfurt am Main, Germany, | PMC10278289 |
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Declarations | PMC10278289 |
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Ethics approval and consent to participate | ICH | ADVERSE EVENTS | This study is conducted in agreement with either the Declaration of Helsinki (in its current version) or the laws and regulations in its current version. The protocol was written, and the study will be conducted according to the ICH Harmonized Tripartite Guideline for Good Clinical Practice. The protocol is approved by the independent ethics committee of the faculty for medicine from the Technische Universität Munich. Before a patient can participate in the trial, he must provide written informed consent. All patients will be informed about the aims of the trial, the possible adverse events and benefits, the procedures and possible risks, the treatment, alternative treatments and the insurance protection. | PMC10278289 |
Consent for publication | Not applicable | PMC10278289 |
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Competing interests | MM | SL received institutional research grants from Bristol-Myers Squibb and Lilly and serves as an advisory board member for Merck, Bristol-Myers Squibb, Merck Sharp and Dohme, Servier, Sanofi and Amgen. MS is an advisory board member for Bristol-Myers Squibb, Lilly, MSD and is a speaker for Bristol-Myers Squibb, Lilly, MSD and Roche. MM received institutional research grants from Bristol-Myers Squibb, Merck, MSD and Amgen and serves as an advisory board member and speaker for Bristol-Myers Squibb, Merck Sharp and Dohme, Servier, Sanofi, Amgen, Lilly, Pfizer and Taiho. All the other authors declare no competing interests. | PMC10278289 |
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References | PMC10278289 |
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Abstract | PMC10632612 |
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Background | hepatitis C | VIRUS, HEPATITIS C | People who use drugs (PWUD) frequently delay or avoid obtaining medical care in traditional healthcare settings. Through a randomized controlled trial, we investigated facilitated telemedicine for hepatitis C virus (HCV) integrated into opioid treatment programmes. We sought to understand the experiences and meanings of facilitated telemedicine and an HCV cure among PWUD. | PMC10632612 |
Methods | We utilized purposive sampling to interview 25 participants, 6–40 months after achieving an HCV cure. We interpreted and explicated common meanings of participants' experiences of an HCV cure obtained through facilitated telemedicine. | PMC10632612 |
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Results | DISORDER, INFECTIOUS DISEASE | Participants embraced facilitated telemedicine integrated into opioid treatment programmes as patient‐centred care delivered in ‘safe spaces’ (Theme 1). Participants elucidated their experiences of substance use and HCV while committing to treatment for both entities. Facilitated telemedicine integrated into opioid treatment programmes enabled participants to avoid stigma encountered in conventional healthcare settings (Theme 2). Participants conveyed facing negative perceptions of HCV and substance use disorder. Improved self‐awareness, acquired through HCV and substance use treatment, enabled participants to develop strategies to address shame and stigma (Theme 3). An HCV cure, considered by PWUD as a victory over a lethal infectious disease, promotes self‐confidence, enabling participants to improve their health and lives (Theme 4). | PMC10632612 |
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Conclusions | Integrating facilitated telemedicine into opioid treatment programmes addresses several healthcare barriers for PWUD. Similarly, obtaining an HCV cure increases their self‐confidence, permissive to positive lifestyle changes and mitigating the negative consequences of substance use. | PMC10632612 |
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Patient and Public Contribution | In this study of patient involvement, we interviewed patient‐participants to understand the meaning of an HCV cure through facilitated telemedicine. Participants from a facilitated telemedicine pilot study provided essential input on the design and outcomes of a randomized controlled trial. Pilot study participants endorsed facilitated telemedicine in a testimonial video. They attended site initiation meetings to guide trial implementation. A Patient Advisory Committee (PAC) ensured that patient participants were active members of the research team. The PAC represented patients' voices through feedback on study procedures. A Sustainability Committee supported public involvement in the research process, including educational opportunities, feedback on implementation, and future sustainability considerations.
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INTRODUCTION | opioid use disorder, HCV disease, HCV) infection | INFECTIOUS DISEASES, VIRUS, HEPATITIS C | People with opioid use disorder frequently experience related infectious diseases, such as hepatitis C virus (HCV) infection. Because of the opioid epidemic, HCV disease burden is the highest amongst the population that uses injection drugs.Previous literature has described people with opioid use disorder considering opioid treatment programmes (OTPs) as comfortable and familiar environments with reduced stigma than is typically encountered in general society.We sought to understand the meaning of facilitated telemedicine for HCV integrated into OTPs from individuals who achieved an HCV cure. To gain insight into their experiences, we interviewed participants an average of 19 months after they achieved an HCV cure. By understanding the common meanings, shared practices, and practical advice related to the facilitated telemedicine model and an HCV cure, we seek to inform future clinical care and policy decisions related to HCV elimination. | PMC10632612 |
METHODS | PMC10632612 |
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Setting and design | We had an opportunity to interview study participants from a recently completed randomized controlled trial to assess HCV treatment through facilitated telemedicine (intervention) integrated into 12 OTPs throughout New York State compared to usual care, offsite referral to a liver specialist (control condition). | PMC10632612 |
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Patient and public contribution | LIVER, ABUSE, RECRUITMENT, CHRONIC LIVER DISEASE | This investigation is a study of patient involvement in which patient‐ participants were interviewed to understand the meaning of an HCV cure. Before the randomized controlled trial, we conducted a pilot study to evaluate the acceptability and feasibility of facilitated telemedicine integrated into OTPs for HCV treatment. When the pilot study concluded, we held a focus group and produced a testimonial video of patients' endorsement of facilitated telemedicine. We presented the testimonial video at site initiation meetings for the randomized controlled trial. The testimonial video, along with in‐person appearances from pilot study participants, promoted site recruitment during the randomized controlled trial. To fully represent patients' voices, we established a Patient Advisory Committee (PAC). As active research participants, the PAC identified areas that required clarification and enabled course‐correction of study procedures.The PAC also identified the importance of HCV education, a task that was addressed through public involvement with the Chronic Liver Disease Foundation and the American Liver Foundation, two organizations whose primary mission is patient and provider education. Additionally, we involved the Office of Addiction Services and Supports (OASAS), the state agency that governs a network of OTPs in New York State, as well as the corresponding federal agency, the Substance Abuse Mental Health Services Administration, in addressing educational concerns related to HCV. In terms of the trial, OASAS assisted in site recruitment, provided input on the study protocol, and approved study procedures before initiation. We also established a Sustainability Committee, comprised of stakeholders from academic institutions, government agencies, nonprofit organizations, and pharmaceutical and diagnostic corporations. The Committee provided feedback on study procedures and made recommendations for the future sustainability of facilitated telemedicine. The public engagement occurred through educational endeavours conducted in collaboration with the New York State Department of Health, such as the development of a statewide telemedicine workgroup and a telemedicine implementation toolkit ( | PMC10632612 |
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Participant recruitment | We used purposive sampling, consistent with hermeneutic phenomenology study design. | PMC10632612 |
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Interview conduct | During the interviews, we inquired about participants' experiences of HCV treatment through facilitated telemedicine in OTPs. We used open‐ended questions and interview prompts to facilitate discussion and elaboration. We asked participants to cite specific examples of the care they received, including what was helpful and not helpful in their pursuit of HCV treatment. We also asked them to make suggestions for future deployment of the facilitated telemedicine model. The interviews were recorded and transcribed using Zoom. Study staff deidentified and verified all transcriptions by comparing their accuracy against the recordings. Interviewers confirmed the final transcript version before analysis. We analyzed the confirmed, deidentified text version. | PMC10632612 |
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Qualitative analysis | liver diseases, hepatitis C | VIRUS, LIVER DISEASES, HEPATITIS C | We used hermeneutic phenomenology to understand human situations as they were experienced within a context of time, place, and situational influences, such as obtaining an HCV cure through telemedicine integrated into an OTP.Interpretation of themes was revealed through experiences, as captured through the participant interviews. All individual interview transcripts served as the data for interpretation. The analysis team included the study's principal investigator (i.e., a physician‐scientist liver diseases expert), a professor of nursing who is an expert in hermeneutic qualitative analysis, and the project manager. The hermeneutics expert guided the analysis. The team interpreted the texts in a reflective process that followed iterative stepsInterpretation of transcripts of participants experiencing facilitated telemedicine for hepatitis C virus treatment. The figure illustrates the hermeneutic phenomenological approach utilized to understand and code the meanings of hepatitis C virus treatment integrated into an opioid treatment programme. | PMC10632612 |
RESULTS | DISORDER, DISORDER | Our interpretation includes four themes and one constitutive pattern to explicate ‘Facilitated Telemedicine for HCV: Addressing Challenges for Improving Health and Life for People with Opioid Use Disorder’. Themes illustrate patients' experiences of (1) embracing facilitated telemedicine in the OTP; (2) committing to the OTP and HCV treatment; (3) facing negative perceptions of HCV and substance use disorder; and (4) engaging in HCV treatment to improve health. | PMC10632612 |
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Theme 1: Embracing facilitated telemedicine in the OTP | hepatitis | DISORDER, VIRUS, HEPATITIS C, LITTLE, HEPATITIS | Participants viewed their OTPs as supportive and trusting environments, qualities that extended to the telemedicine encounter and provider. Overall, participants were enthusiastic about healthcare delivery through facilitated telemedicine. One participant explained that onsite facilitated telemedicine for healthcare delivery mitigated the apprehension he/she faced as a substance user when referred to offsite healthcare settings. ‘I would be more comfortable at my methadone clinic than going to a primary care doctor or the emergency room’. Participants elaborated how facilitated telemedicine expanded healthcare access in a convenient setting and removed barriers to care, such as transportation:I honestly wouldn't have done it [HCV treatment]; I would have put it off. Telemedicine saves so much time, as opposed to getting in the car, going to the doctor, waiting in line, [and] checking in. It's been a wonderful experience.Participants were initially anxious about telemedicine encounters. After the study‐supported case manager provided HCV education that also addressed misconceptions and assured privacy and confidentiality during the encounter, they became more accepting of facilitated telemedicine. One participant elaborated:They didn't push anything, they explained how it works and broke it down in [an] understandable way. They're very discreet… It's a one‐on‐one type of atmosphere.The case manager was also an onsite telemedicine facilitator as well as a convenient go‐to person who alleviated study participants' fears and concerns, encouraging and integrating patient‐centred care into the OTP for hepatitis CWhen I got my [test] results that I have hepatitis C again, [the case manager] called me to the office and spoke to me in person [about] treatment. She explained [that the] new medicine is not the old medicine.The case managers leveraged the caring atmospheres of the OTP for effective facilitated telemedicine:The case manager made me feel the most comfortable that I've ever felt, even though they knew I was an IV drug user. They actually will take your hand if you're having a bad day and give you a hug. Little things like that, they're constantly smiling, telling you good things about how you're doing, showing you the levels [of the virus], that just makes you feel good.Participants also valued the integration of HCV treatment within the OTP that provided seamless interactions between the case manager and OTP staff:Everybody that participated, doctors, workers, I couldn't ask for a better group. Always checking on you… I still tell people to this day how excellent it was.Participants also valued onsite care and summarized advantages that are related to colocation of HCV care within the OTP:Even if you're somebody that goes to the clinic every day, being able to get your [HCV] dose at the window is perfect, because a lot of people forget about taking their dose. You're already there and you're already taking your [substance use disorder] medication. | PMC10632612 |
Theme 2: Committing to the OTP and HCV treatment | depression, vulgar’, anxiety | DISORDER | Participants described their experiences of substance use as losing control of their lives. One participant described his substance use as a primary need ‘to feel a high. [You] will spend all your money, [and] the next day, you're broke’. When experiencing substance use disorder, participants also struggle with symptoms of anxiety and depression that manifest in their attitudes of impatience, short attention spans, and ‘loud and vulgar’ behaviour. Once participants decided to pursue treatment for substance use disorder, they enroled in the OTP ‘trying to get clean and sober’, as the programme provides methadone as an evidence‐based treatment to manage withdrawal symptoms and counselling to address mental health issues, as one participant explained:There's a lot of ways to beat addiction. It is not just ‘give me a bottle of methadone and let me be on my way’. Sometimes people need to talk… Groups are very supportive.One participant explained the need to commit themselves to treatment for both substance use and HCV, ‘It's not mandatory, most of the people [are] there on their own will. Help is there, but [it is] up to you’. Participants depicted the wide array of OTP services in addition to methadone and counselling.[They] can refer you to mental health services… They also have job training programmes… Having a counselor to help with [individual] needs… one‐on‐one is the therapeutic value.Almost uniformly, participants considered the OTP a destigmatizing community where they felt positive reinforcement from frequent contact with OTP staff. Participants appreciated that OTP staff, including counsellors who address them by their first names, nurture mutual respect and understand the nature of substance use disorder:Everybody there really cares and it's personal, we're not just numbers. I can trust them enough to speak [about] what I was going through, and they helped me out a lot.Counsellors provided the first line of support, not only for substance use treatment, but they also facilitated patient engagement in HCV treatment through facilitated telemedicine. The net effect of the OTP is to promote recovery from substance use disorder and co‐occurring conditions, such as HCV, and improve self‐awareness, ‘[The treatment goal] is less of the addiction part and more of It is hard to get someone to come to the programme but stay in the programme as long as it takes because the OTP is an intricate part of your life. | PMC10632612 |
Theme 3: Facing negative perceptions of HCV and substance use disorder | Participants referred to themselves as ‘addicts’, a learned label and attitude associated with substance use that reinforces negative self‐perceptions. This attitude was revealed in the language that participants used to refer to themselves as ‘dirty’ or ‘clean’ depending on their current state of substance use, as one participant reflected:A lot of addicts feel the same way [about their substance use]… You can't imagine the horror that I go through… It's hard to explain unless you're familiar with addiction personally. | PMC10632612 |
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Subtheme 3a: Confronting poor relations with external healthcare providers | prejudice, pain | Participants revealed that one of the advantages of facilitated telemedicine situated in the OTP is that it permits them to circumvent the obstacles they face in traditional healthcare settings where they are ‘labelled as a drug user’. One participant related a similar sentiment when seeking healthcare in a conventional healthcare settingWhen they found out that I was an IV drug user, the whole atmosphere changes… And that's one of the reasons I never sought treatment for [HCV].Another participant cited a story about seeking care for injury‐associated pain in the hospital where they perceived hospital workers' prejudice when checking the opioid registry.[I was] red flagged every single time. When you try to get pain pills, [they think] you fake it because you can't afford the drugs on the streets. You have to go by the [healthcare] system [rules].Another participant shared his/her experience with a provider that demonstrated a misunderstanding of methadone's role to alleviate withdrawal symptoms:[The dentist] actually refused to give me Novocain because I was on methadone… Obviously I switched dentists… A lot of it is knowledge‐related and [lack of] education.The shame and stigma of substance use led participants to delay or entirely avoid seeking healthcare in conventional settings. As the participants learned of the negative consequences of disclosing their methadone status to providers, they also realized that practicing nondisclosure was a strategy to avoid the shunning when seeking healthcare in conventional settings:I don't usually bring it up, unless I absolutely have to… If I'm in a medical setting, obviously I want them to know what medications I'm on, but in my normal discourse with people, I don't bring up that I'm on methadone. | PMC10632612 |
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Subtheme 3b: Enduring negative perceptions of substance use disorder in society | opioid use disorder, drug abuse, drug addiction, Drug [addiction | DISORDER, DISEASE | Participants related experiences in society where they were judged for their substance use disorder as a moral failing, a misunderstanding of the basis of substance use disorder as a physiologic medical condition, as one participant summarized:A lot of people have no education about drugs, all they know is from movies… Drug [addiction] is a disease… People think it's not a disease or that this is what you want to do, and you can stop at any moment with no problem. And if you don't want to stop, then you are a drug addict, you're a bad person and selfish. Of course, it's wrong.A participant shared his/her view of society's assumptions about substance use as a psychological condition that persists even if someone is well on their way to recovery. ‘It is in their mind… They assume that what you were is still a part of you now’. Another participant concurred and clarified society's misunderstandings of people with substance use disorder:[Others have] misconceptions about drug abuse, they think an addict is somebody who hangs [out] in the street all day. I work, I've worked all my life. I come from a family that worked, I went to college. Yet it's the stigma, the attitudes and preconceptions that come with drug addiction.One participant also elaborated on societal misconceptions surrounding the treatment of substance use disorder, specifically methadone:[Methadone] does raise eyebrows… I'll have to explain about being on [methadone], it's not smoking crystal meth… Sometimes, that's what police officers will think… You have to actually say ‘I am Indeed, participants learned to state that they were ‘Thus, although opioid use disorder affects every aspect of participants' lives, through treatment of substance use disorder and co‐occurring conditions, such as HCV, participants develop self‐awareness of the negative attitudes of those around them and begin to develop strategies to mitigate the shame. | PMC10632612 |
Subtheme 3c: HCV diagnosis as shameful | opioid addiction | DISORDER | As participants progress through treatment for opioid addiction, they develop self‐awareness of the misunderstandings of substance use disorder, associated comorbid conditions such as HCV, and of the negative attitudes held by people outside of the OTP. ‘They think that because you're on methadone, you're sh**, you're dirt, you're lower than low’.Participants' narratives portrayed feelings of embarrassment and doom related to a diagnosis of HCV. ‘[HCV] is not only dirty but disgusting, because people may think that anyone that got [it] was using needles for drugs’. Because of these sentiments, some participants initially delayed seeking HCV treatment. ‘I didn't tell anybody, no family members or anything’. Because of HCV‐related shame and stigma, patients do not feel comfortable discussing an HCV diagnosis with others and voiced their concerns related to privacy and confidentiality surrounding an HCV diagnosis and treatment. | PMC10632612 |
Theme 4: Engaging in HCV treatment to improve health | headaches, anxiety, shakes, HCV infection, pain, hepatitis C, sweats, hepatitis | DISEASE, HEPATITIS C, HEPATITIS | Several participants were motivated to pursue HCV treatment because they viewed HCV infection as a lethal disease, and they personally knew friends and family who died of HCV:I don't want to pass hepatitis C to nobody… I know that hepatitis C is hard. I got family, my niece passed away [from] hepatitis C… I [want] to get the treatment for hepatitis C.Participants recounted stories of prior HCV treatment regimens (i.e., interferon) that were arduous and highly ineffective. The education that was provided during the study informed them of modern HCV treatment regimens with high efficacy and minimal side effects, potentiating an HCV cure and hope for the future:Before I knew they had a cure for HCV, I thought I was doomed… If I still got hepatitis C, I am not going to last long. It makes no sense to see a doctor because the doctor is not going to do anything for me. Until you guys [study personnel] showed up… I was tired, I was fatigued. It was a lot of symptoms going on with me.Furthermore, participants commented on how rapidly HCV treatment, once initiated, improved their symptoms and quality of life:[It helped] tremendously, within a month and a half, I started seeing results. I started feeling different… My legs are moving faster… I feel amazing.Achieving an HCV cure enabled participants to start a new beginning in their lives by ‘planning new goals with a brighter outlook’. The HCV cure also enabled participants to improve their self‐confidence, ‘It's definitely made me feel a lot better, more confident’. Increased energy and newfound self‐confidence enabled people who achieved a cure to pursue many new directions. As one participant commented:HCV treatment was a catalyst for getting life under control and for changing many things in my life. I'm just glad that they were able to find a cure for it.Several participants explained specifically how the cure affected the rest of their lives. For example, one participant appreciated the cure as it decreased anxiety:I don't have the thought in my head anymore that I got this thing in my body that's killing [me]… I think it is a godsend. In eight weeks, you could help somebody prolong their life.Another participant shared his/her newfound joy in life after having been cured of HCV:I wake up every morning happy, joyful, [drug‐]free. I wake up not worrying about the pain, the suffering, the shakes, the headaches, the sweats, the disillusions, the lies that go through my mind of getting one more [high]. This programme granted that. Freedom in choices for me today!Several participants discussed the importance of supporting and providing others the chance to use the facilitated telemedicine model. Participants discussed sharing their successes with others via ‘a peer pipeline [and] spreading the word about HCV treatment to help others, anything to help mankind’. The peer pipeline was emphasized as a way to inform others of the importance of an HCV cure:I think [by getting] the word out, a lot more people would do the treatment… I have five people who have reached out to me that want to get treatment.Participants vocalized their understanding of the need to speak freely about HCV treatment, ‘Telling others about treatment; awareness of having knowledge [that can] be disseminated to benefit others’.Besides the peer pipeline, participants recommended not only expansion of facilitated telemedicine to other methadone programmes, but to other substance use treatment programmes as well.A lot of people with this problem are not on methadone, they're not aware of it, or their methadone clinic doesn't deal with it. There [should be] a way [for] methadone [or] addiction systems [to share] the fact ‘Hey, there is something you could do’.Not only did participants recount their own experiences of attempting to convince family members, peers, and their programmes of HCV treatment benefits, some participants viewed an HCV cure as a steppingstone toward a career change. One participant commented, ‘I'm trying to become a counsellor because I feel I have so much to offer’. | PMC10632612 |
Constitutive pattern | PMC10632612 |
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Facilitated telemedicine for HCV: Addressing challenges for improving health and life for people with opioid use disorder | addict”’.‘If, go”’.‘Confidentiality, pain, hepatitis C, drug abuse, hepatitis | HEPATITIS C, VIRUS, SAID, HEPATITIS | Participants underscore the convenience and confidentiality of facilitated telemedicine integrated into the OTP, providing access to patient‐centred care, and circumventing external providers. They embrace facilitated telemedicine as promoting a therapeutic relationship between patients and telemedicine providers. These relationships are facilitated by a case manager who builds trust with patients, answers their questions, and facilitates the telemedicine encounter (Additional supportive participant quotations.‘I think it [telemedicine] was great for me because I don't like doctors, I don't like hospitals, and to be able get this done while coming into the clinic was wonderful’.‘Telemedicine is a good experience, just like [the doctor] was there, easy conversation’.‘I know it's going to take a while for telemedicine to [go] into effect, but it would be wonderful because so many more people will get treatment’.‘Phlebotomist and case manager were very helpful. They were very knowledgeable; they were gentle with me because I am an emotional type of person’.‘[We] talked about it, and I was scared. He [case manager] told me I was going to be all right. He helped me get through it. He kept on telling me “You're going to be fine”’.‘I don't have to go [to outside providers] and wait two hours just to [be] sent home with ibuprofen and a cup of water. I could call the [case manager] to explain what was going on, and I really appreciate that’.‘I felt that they were involved with me every step of the process… When I had to give blood, they told me exactly what it was for. They told me how I should be feeling at this point, and three weeks down the road, how I should be feeling’.‘The first moment, I [was] scared. After I started treatment, I felt good. I feel comfortable with the medicine. The doctor explained everything, and I understood I needed the treatment, and I said “let's go”’.‘Confidentiality, as far as people not knowing my situation, they're very discreet… They do a really good job not discussing other clients' situations. It's a one‐on‐one type of atmosphere’.‘The counselors would be walking around [and] if they see you, they would say, “I just wanted to say hi” and “When you are done getting dosed, can we sit down for two minutes? I just want to know how your day is going”. They are involved 100%’.‘I trust the [OTP] community, but it took some time for me to trust them. [At first] I didn't want to hear nothing… I just wanted to come in and leave. The counselors took their time; they were very patient, even when I was disrespectful… They changed my life around, the counselors, because I was heading to a graveyard’.‘The methadone clinic is the best place that I've ever been to. This is the most comfortable I've ever been in a setting with so many people’.‘Once I got addicted to the pain pills… it took years of counselling and medication… If I were to stop taking methadone [which] I am nervous to do… I feel that I would go right back to the opiates’.‘I wish you had known me 20 years ago. You would be amazed at the transformation, the change through this programme. When I first came here, I was a total mess’.‘I had a negative attitude about myself, people around me, doctors and nurses. I took a good look at myself, and I went back to college, and I graduated. It was a counsellor in the methadone programme that changed me. I never looked back. I changed my ways, and it was for the better. And this [programme] made me the person I am today’.‘The experience with the methadone is absolutely phenomenal compared to what I was doing on the street’.‘It's a great programme and saved my life, methadone is turning my life around. I've been here two years, hard to come, harder to stay, [stay] as long as it takes’.‘Going to the hospital and knowing you're on methadone, they think you're a heroin addict. People try to hide it but they look at you a little different, “Oh, here comes another addict”’.‘If it's somebody new [physician] and with addicts, I get the feeling that doctors think that we're always doctor‐shopping or trying to get drugs… Sometimes it happens, and sometimes it's uncomfortable’.‘I've been with my doctor a couple years now, but when they find out you're on methadone, they don't want to give you the meds that you need’.‘When I go to the emergency room, I need to tell them [about methadone]. They need to know that I'm on methadone because it could be a contraindication to another medication’.‘I've spoken to other doctors who tell me that addiction providers are considered the bottom of the totem pole [in] the medical field… How much training does the doctor have on drug treatment? Misconception about drug abuse, period’.‘I have had an incident when I said, “I'm on methadone” and they [police] look you up and down “what the hell kind of drug are you talking about? Are you smoking crystal meth?” and I've been pulled out of my vehicle… It makes me slow down and think’.‘Certain people, I won't talk to them, and they don't talk to me. People get off the train, and we're having coffee on the corner, some of them look at us and think that we're all addicts, we're not’.‘I say, "I'm in the methadone programme"… They know exactly what you're talking about… If you [say] I'm on methadone, they start questioning you, and they don't know what you're talking about… I'm telling people that I am in the programme, and I'm physically in here, not on it’.‘I was never an IV drug user, so how did I get hepatitis? The doctor told me you could get it by sharing a straw. I automatically assumed that [HCV] went with IV drug use’.‘Nobody told me there was a treatment and that I can be cured. I thought it was something I had to live with for the rest of my life’.‘Now, when you're tired, you don't think anything's wrong. But once you find out you have it [HCV], they can get you on the right medication, get you out on the right path, and you will be fine’.‘I have kids and I didn't want to have an old razor laying around… I wanted to get my health back on track, so I said yes to the study [and HCV treatment]’.‘Overall, it was a great experience. I had no problems with the medication. I was very fearful going into it because of the past, how the treatment used to be literally like chemo. I don't think people understand how different this new treatment is’.‘Lots of patients [are] still suffering from hepatitis C, and they [are] not aware of the new medicine… [they] still think that it's the old, long, heavy treatment’.‘I got more energy. I feel rejuvenated… I feel 100% better… By getting cured from hepatitis C that prolonged my life’.‘The nurse said “you no longer come up as infected with hep C” so that was a great feeling, like a bond to not expose myself again. I know people that have… I told them, listen, it works, and you'll be free of that and then live a healthier life’.‘Before the medicine, I was tired all the time. I didn't want to get out of bed to do the things that I love: fishing, hunting, camping, or going out to dinner. Now, with methadone [and] hepatitis treatment being over, I feel amazing. I'm writing a book on my life… I'm 483 pages into it, and I just need to get a publisher. I'm getting married next month; I'm buying a house to fix up for me and my wife, and things are going the way that they should be’.‘Right now, my fiancé's making scrambled eggs, steak, potatoes, and French toast. We have our goals, we have our days planned out. Before I would be lying in bed, and she would have to bring breakfast to me because of the hepatitis and how much it takes out of you. Everything's back on track, and I feel amazing’.Abbreviations: HCV; hepatitis C virus, OTP; opioid treatment programme.Study themes as revealed by participant interviews. Integrating facilitated telemedicine for hepatitis C virus treatment into opioid treatment programmes facilitates commitment to substance use and HCV treatment enabling participants to mitigate negative perceptions of these conditions and leading to improved health. | PMC10632612 |
DISCUSSION | hepatitis C, HCV infection, anxiety | DISORDER, VIRUS, DISEASE, HEPATITIS C, SEPARATION, HEPATITIS C | Participants revealed how facilitated telemedicine expanded healthcare access in the OTP, which they consider a ‘safe space’ that is supportive, trusting, and destigmatizing. Similarly, other research described OTPs as accepting and comfortable environments.Although substance use disorder is a physiologic medical condition, participants face perceptions of shame due to negative assumptions about their substance use. They perceived HCV infection as ‘dirty’, resulting in additional anxiety and shame. Participants described experiences of humiliation and shame that add nuanced understanding to other research describing stigma leading to low self‐esteem, social isolation, and reduced intimacy.The consequences of substance use disorder, including experienced and anticipated shame, interfere with the pursuit of HCV treatment. In the literature, shame or stigma is conceptualized as a process of separation stemming from discrimination against individuals who exemplify characteristics outside the norm.Patient experiences of challenges and strategies to overcome challenges for hepatitis C virus treatment pursuit.
Distrusting the healthcare system.Lacking knowledge and understanding of telemedicine.
Seeking a family‐like community environment in which to pursue treatment for substance use disorder and HCV.Promoting a therapeutic alliance with providers with regular communication and positive reinforcement.Benefitting from supportive case management throughout the HCV treatment course.Educating and familiarizing patients about telemedicine.Confronting poor relations with external providersShaming experiences as a barrier to seeking treatment in traditional healthcare settings (i.e., emergency department, primary care).Disclosing substance use status to healthcare providers engendering negative feedback and shaming.
Using situational awareness and nondisclosure if necessary.Communicating effectively to reflect substance use disorder treatment goals, for example, ‘in a methadone programme’ versus ‘on methadone’.Educating and training providers to understand substance use disorder treatments and the effects of stigma.Supporting HCV care integrated into the OTP.Evaluating consequences of social structures supporting disparities.
Enduring negative perceptions of substance use disorder in societyExperiencing the misconception of methadone as just another drug.Limited public knowledge of substance use disorder as a medical condition, that is, blaming, shaming as moral failures.
Educating others on substance use disorder as a medical disease.Education on MOUD and counselling as effective, evidence‐based treatments.Increasing public awareness of the experiences of shaming due to substance use, including in law enforcement and the criminal justice system.Using appropriate language to describe substance use disorder treatment.
HCV as shamefulBelieving misconceptions of substance use disorder and HCV treatments.Recognizing the negative view of HCV.Knowing others who have died from HCV.
Gaining awareness of substance use disorder as a medical disease.Gaining knowledge of innovative treatment modalities for achieving an HCV cure.Maintaining privacy and confidentiality regarding HCV.Changing policies to support HCV treatment as integrated care within the OTP.
Believing that HCV treatment is unsafe and ineffective (misconceptions).
Listening to successfully treated peers.Improving self‐confidence, self‐worth, and overall wellness.Obtaining an HCV cure is an accomplishment indicative of progress in addressing substance use disorder.An HCV cure promoting improvement in overall health.Abbreviations: HCV, hepatitis c virus; OTP, opioid treatment programme; MOUD, medication for opioid use disorder.Participants also described how an HCV cure was considered a victory, promoting self‐confidence, and enabling the pursuit of beneficial activities for themselves and others. Increased self‐awareness and self‐confidence promoted the development of strategies for participants to address health and life issues, consistent with observations by others.Our study has several strengths. One is the specific elaboration of the manifestations of substance use disorder shame (stigma) (i.e., self, HCV, healthcare, and society) and how these were addressed through facilitated telemedicine and an HCV cure. Addressing specific stigma components provides nuanced understanding, addressing the critique of a recent thematic synthesis that identified that previous investigation of stigma in HCV has largely been assumed and implicit. | PMC10632612 |
CONCLUSIONS | DISORDER | Participants' stories described how the trusted environment of the OTP promotes substance use disorder treatment. Facilitated telemedicine, along with the integrated case manager and interdisciplinary team of OTP staff, provide patient‐centred care for HCV, while simultaneously addressing participants' concerns. The culmination of these activities, an HCV cure, promotes participants' self‐confidence, enabling the pursuit of activities to improve their health and their lives. Practical advice and best practices related to facilitated telemedicine may be informative in expanding future clinical care and policy decisions related to HCV elimination. | PMC10632612 |
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