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  • Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma – protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial

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Surgery
Protocol
Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma – protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial
  1. James J M Loan1,2,
  2. Andrew Bacon3,
  3. Janneke van Beijnum4,
  4. Pragnesh Bhatt5,
  5. Anna Bjornson6,
  6. Nicole Broomes7,
  7. Alistair Bullen8,
  8. Diederik Bulters7,
  9. Julian Cahill9,
  10. Emmanuel Chavredakis10,
  11. Francesca Colombo11,
  12. Mihai Danciut6,
  13. Ronneil Digpal7,
  14. Richard J Edwards12,
  15. Lucie Ferguson13,
  16. Laura Forsyth8,
  17. Ioannis Fouyas2,
  18. Vijeya Ganesan14,
  19. Patrick Grover15,
  20. Nihal Gurusinghe11,
  21. Peter S Hall16,
  22. Kirsty Harkness3,
  23. Lauren S Harris17,
  24. Tom Hayton18,
  25. Adel Helmy19,20,
  26. Daniel Holsgrove21,
  27. Peter J Hutchinson19,20,
  28. Anil Israni22,
  29. Elaine Kinsella8,
  30. Steff Lewis8,
  31. Sohail Majeed5,
  32. Conor Mallucci22,
  33. Nitin Mukerji13,
  34. Ramesh Nair23,
  35. Aileen R Neilson8,
  36. Marios C Papadopoulos24,
  37. Matthias Radatz9,
  38. Alex Rossdeutsch3,
  39. Saba Raza-Knight11,
  40. Jacqueline Stephen8,
  41. Andrew Stoddart8,
  42. Mario Teo25,
  43. Carole Turner19,20,
  44. Julia Wade26,
  45. Daniel Walsh27,28,
  46. David White29,
  47. Phil White30,
  48. Jack Wildman25,
  49. Oliver Wroe Wright27,
  50. Christopher Uff31,
  51. Shungu Ushewokunze32,
  52. Raghu Vindlacheruvu17,
  53. Neil Kitchen15,
  54. Rustam Al-Shahi Salman1,2,8
  55. on behalf of the Cavernomas A Randomised Effectiveness (CARE) pilot trial collaborators
    1. 1Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK
    2. 2Department of Clinical Neurosciences, Royal Infirmary of Edinburgh, Edinburgh, UK
    3. 3Royal Hallamshire Hospital, Sheffield, UK
    4. 4Neurosurgery, University Hospital of Wales, Cardiff, UK
    5. 5Aberdeen Royal Infirmary, Aberdeen, UK
    6. 6Hull Royal Infirmary, Kingston upon Hull, UK
    7. 7University Hospital Southampton NHS Foundation Trust Wessex Neurological Centre, Southampton, UK
    8. 8Edinburgh Clinical Trials Unit, The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK
    9. 9National Centre for Stereotactic Radiosurgery, Royal Hallamshire Hospital, Sheffield, UK
    10. 10Walton Centre for Neurology and Neurosurgery, Liverpool, UK
    11. 11Royal Preston Hospital, Preston, UK
    12. 12Bristol Royal Hospital for Children, Bristol, UK
    13. 13James Cook University Hospital, Middlesbrough, UK
    14. 14Developmental Neurosciences Department, Great Ormond Street Hospital for Children, London, UK
    15. 15The National Hospital for Neurology & Neurosurgery, London, UK
    16. 16Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
    17. 17Queen’s Hospital, Romford, UK
    18. 18Queen Elizabeth Hospital, Birmingham, UK
    19. 19Clinical Neurosciences, University of Cambridge, Cambridge, UK
    20. 20Addenbrooke’s Hospital, Cambridge, UK
    21. 21Centre for Clinical Neurosciences, Salford Royal Hospital Manchester, Salford, UK
    22. 22Alder Hey Children’s Hospital, Liverpool, UK
    23. 23Charing Cross Hospital, London, UK
    24. 24Department of Neurosurgery, Atkinson Morley Wing, St George’s Hospital, London, UK
    25. 25Department of Neurosurgery, Southmead Hospital, Bristol, UK
    26. 26Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
    27. 27King’s College Hospital, London, UK
    28. 28Institute of Psychiatry Psychology & Neuroscience, King’s College London, London, UK
    29. 29Cavernoma Alliance, Watlington, UK
    30. 30Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK
    31. 31The Royal London Hospital, London, UK
    32. 32Sheffield Children’s Hospital NHS Foundation Trust, Sheffield, UK
    1. Correspondence to Professor Rustam Al-Shahi Salman; rustam.al-shahi{at}ed.ac.uk

    Abstract

    Introduction The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was ‘Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?’ This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT.

    Methods and analysis We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress.

    Ethics and dissemination This study was approved by the Yorkshire and The Humber—Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group.

    Trial registration number ISRCTN41647111.

    • Neurosurgery
    • Stroke
    • NEUROSURGERY
    • Paediatric neurology
    • Adult neurology
    • Clinical Trial
    https://creativecommons.org/licenses/by/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

    https://doi.org/10.1136/bmjopen-2023-075187

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      Footnotes

      • Twitter @James_JM_Loan, @bullen_ali, @BleedingStroke

      • Collaborators Royal Infirmary Edinburgh - Ioannis Fouyas, Allan MacRaild, Jessica Teasdale, Michelle Coakley, James Loan, Rustam Al-Shahi Salman, Paul Brennan, Drahoslav Sokol, Anthony Wiggins, Chandru Kaliaperumal, Mairi MacDonald and Sarah Risbridger; St.George’s Hospital - Marios Papadopoulos, Siobhan Kearney, Ravindran Visagan, Ellaine Bosetta and Hasan Asif; Great Ormond Street Hospital - Greg James, Aswin Chari, Vijeya Ganesan, Martin Tisdall, Christin Eltze, Zubair Tahir and Sanjay Bhate; National Hospital Neurology and Neurosurgery - Patrick Grover, Azra Banaras, Sifelani Tshuma, Neil Kitchen, William Muirhead, Ciaran Scott Hill, Rupal Shah, Thomas Doke, Rebecca Hall and Sonny Coskuner; Royal Hallamshire Hospital - Andrew Bacon, Kirsty Harkness, Emma Richards, Jo Howe, Christine Kamara, Jonathan Gardner, Madalina Roman, Mary Sikaonga, Matthias Radatz, Julian Cahill, Alex Rossdeutsch, Varduhi Cahill, Imron Hamina and Kishor Chaudhari; Addenbrooke’s Hospital - Adel Helmy, Liliana Chapas, Silvia Tarantino, Karen Caldwell, Mathew Guilfoyle, Smriti Agarwal, Daniel Brown, Sarah Holland and Tamara Tajsic; Alder Hey Hospital - Conor Mallucci, Anil Israni, Rachael Dore, Taya Anderson, Dawn Hennigan, Shelley Mayor, Laura O’Malley and Samantha Glover; Aberdeen Royal Infirmary - Pragnesh Bhatt, Janice Irvine, Sohail Majeed, Sandra Williams, John Reid, Annika Walch, Farah Muir and Eng Tah Goh; Queen Elizabeth Hospital, Birmingham - Tom Hayton, Arlo Whitehouse, Andrew McDarby, Michelle Bates, Rebecca Hancox, Edward White and Claudia Kate Auyeung; Birmingham Children’s Hospital - William B Lo and Julie Woodfield; Southmead Hospital - Mario Teo, Jack Wildman, Kerry Smith, Elizabeth Goff, Deanna Stephens, Borislava Borislavova, Ruth Worner, Sandeep Buddha and Philip Clatworthy; Bristol Royal Hospital for Children - Richard Edwards, Karen Coy, Lisa Tucker, Sandra Dymond, Andrew Mallick, Rebecca Hodnett and Francesca Spickett-Jones; University Hospital Wales - Janneke van Beijnum, Paul Leach, Tom Hughes, Milan Makwana, Khalid Hamandi, Dymona McAleer and Belinda Gunning; Hull Royal Infirmary - Mihai Danciut, Emma Clarkson and Anna Bjornson; Walton Centre - Emmanuel Chavredakis, Debbie Brown, Giannis Sokratous, John Williamson, Cathy Stoneley, Andrew Brodbelt, Jibril Osman Farah and Sarah Illingworth; Charing Cross Hospital, London - Ramesh Nair, Sophie Hunter, Niamh Bohnacker, Rosette Marimon, Lydia Parker, Oishik Raha and Puneet Sharma; King’s College Hospital, London - Daniel Walsh, Oliver Wroe Wright and Sabina Patel; Salford Royal Hospital - Dan Holsgrove, Danielle McLaughlan, Tracey Marsden, Francesca Colombo, Kathryn Cawley, Hellen Raffalli and Saba Raza-Knight; Manchester Children’s Hospital - Ian Kamaly-Asl, Felicia Jennings, Nicola Phillips, Imedla Mayor, James Stewart, Dipek Ram, Rebecca Keeping, Grace Vassallo and Katie Hennessy; James Cook University Hospital - Nitin Mukerji, Emanuel Cirstea, Susan Davies, Venetia Giannakaki, Ammar Kadhim, Oliver Kennion, Md Moidul Islam, Lucie Ferguson and Manjunath Prasad; Royal Victoria Infirmary, Newcastle - Nicholas Ross, Beth Atkinson, Cheryl Webster, Michelle Fawcett, Vicky Slater and Saffnan Mohamed; Royal Preston Hospital - Nihal Gurusinghe, Saba Raza Knight, Terri-Louise Cromie, Allan Brown, Sonia Raj, Ruth Pennington, Charlene Campbell, Shakeelah Patel and Francesca Colombo; Queen’s Hospital, Romford - Raghu Vindlacheruvu, Anthony Ghosh, Teresa Fitzpatrick and Lauren Harris; Sheffield Children’s Hospital - Shungu Ushewokunze, Sarah Ali, John Preston, Carole Chambers and Mohammed Patel; Southampton General Hospital - Diederik Bulters, Ronneil Digpal, Winnington Ruiz, Mirriam Taylor, Divina Anyog, Katarzyna Tluchowska, Jackson Nolasco, Daniel Brooks, Kleopatra Angelopoulou, Bethany Welch and Nicole Broomes; Royal Stoke Hospital - Howard Brydon, Ida Ponce, Louis Taylor, Lucy Bailey, Mia Marsden, Claire Hudson, Angelene Cope, Jack Lee, Deepthy Blesson and Rachel Sutton; Leeds General Infirmary – Ian Anderson, Mary Kambafwile, Linetty Makawa, Jade McAndrew and Atul Tyagi; Royal London Hospital - Christopher Uff and Geetha Boyapati.

      • Contributors Conceptualisation: RA-SS and NK, supported by JJML, VG, PSH, KH, PJH, EK, SL, CM, ARN, MR, JS, AS, CT, JWa, DWh, and PW. Methodology: JJML, VG, PSH, KH, PJH, EK, SL, CM, ARN, MR, JS, AS, CT, JWa, DWh, PW, NK and RA-SS. Project administration: JJML, ABj, JvB, PB, ABu, NB, DB, JC, EC, FC, MD, RD, RJE, LFo, LFe, IF, VG, PG, NG, KH, LSH, TH, AH, DH, PJH, AI, EK, SM, CM, NM, RN, MCP, MR, AR, SR-K, MT, CT, JWa, DWh, DWa, PW, JWi, OWW, CU, SU, RV, NK and RA-SS. Funding Acquisition: RA-SS, supported by LFo, EK, and NK. Writing—original draft: JJML and RA-SS. Writing—review and editing: All. Supervision: RA-SS and NK.

      • Funding The CARE pilot trial is funded by the National Institute for Health and Care Research (NIHR128694), which requires publication of the trial protocol but had no other role in manuscript preparation or the decision to publish.

      • Competing interests PW declares institutional unrestricted educational grant funding for a stroke reperfusion course from Stryker, Penumbra and Medtronic. MR declares that he is a Senior Clinician of the National Centre for Stereotactic Radiosurgery.

      • Patient and public involvement Patients and/or the public were involved in the design, conduct, reporting, and dissemination plans of this research. Refer to the Methods section for further details.

      • Provenance and peer review Not commissioned; peer reviewed for ethical and funding approval prior to submission.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.