Medical management and surgery versus medical management alone for symptomatic cerebral cavernous malformation (CARE): a feasibility study and randomised, open, pragmatic, pilot phase trial
Authors: Madeleine Eriksson, Raza Hayat, Elaine Kinsella, Katherine Lewis, David CS White, Julia Boyd, Alastair Bullen, Morag Maclean, Andrew Stoddart, Sandra Phair, Helen Evans, Jo Noakes, Debra Alexander, Catriona Keerie, Christopher Linsley, Garry Milne, John Norrie, Nicola Farrar, Alba X Realpe, Jenny L Donovan, Janet Bunch, Kathryn Douthwaite, Simon Temple, James Hogg, David Scott, Pat Spallone, Ian Stuart, Joanna M Wardlaw, Jeb Palmer, Eleni Sakka, Nitin Mukerji, Emanuel Cirstea, Susan Davies, Venetia Giannakaki, Ammar Kadhim, Oliver Kennion, Moidul Islam, Lucie Ferguson, Manjunath Prasad, Andrew Bacon, Emma Richards, Jo Howe, Christine Kamara, Jonathan Gardner, Madalina Roman, Mary Sikaonga, Julian Cahill, Alex Rossdeutsch, Varduhi Cahill, Imron Hamina, Kishor Chaudhari, Mihai Danciut, Emma Clarkson, Anna Bjornson, Diederik Bulters, Ronneil Digpal, Winnington Ruiz, Mirriam Taylor, Divina Anyog, Katarzyna Tluchowska, Jackson Nolasco, Daniel Brooks, Kleopatra Angelopoulou, Bethany Welch, Nicole Broomes, Ioannis Fouyas, Allan MacRaild, Chandru Kaliaperumal, Jessica Teasdale, Michelle Coakley, Paul Brennan, Drahoslav Sokol, Anthony Wiggins, Mairi MacDonald, Sarah Risbridger, Pragnesh Bhatt, Janice Irvine, Sohail Majeed, Sandra Williams, John Reid, Annika Walch, Farah Muir, Janneke van Beijnum, Paul Leach, Tom Hughes, Milan Makwana, Khalid Hamandi, Dympna McAleer, Belinda Gunning, Daniel Walsh, Oliver Wroe Wright, Sabina Patel, Nihal Gurusinghe, Saba Raza-Knight, Terri-Louise Cromie, Allan Brown, Sonia Raj, Ruth Pennington, Charlene Campbell, Shakeelah Patel, Francesca Colombo, Mario Teo, Jack Wildman, Kerry Smith, Elizabeth Goff, Deanna Stephens, Borislava Borislavova, Ruth Worner, Sandeep Buddha, Philip Clatworthy, Richard Edwards, Evangeline Clayton, Karen Coy, Lisa Tucker, Sandra Dymond, Andrew Mallick, Rebecca Hodnett, Francesca Spickett-Jones, Patrick Grover, Azra Banaras, Sifelani Tshuma, William Muirhead, Ciaran Scott Hill, Rupal Shah, Thomas Doke, Rebecca Hall, Sonny Coskuner, Laura Aslett, Raghu Vindlacheruvu, Anthony Ghosh, Teresa Fitzpatrick, Lauren Harris, Tom Hayton, Arlo Whitehouse, Andrew McDarby, Rebecca Hancox, Claudia Kate Auyeung, Ramesh Nair, Rhys Thomas, Heather McLachlan, Athanasia Kountourgioti, Guillelme Orjales, Jan Kruczynski, Sophie Hunter, Niamh Bohnacker, Rosette Marimon, Lydia Parker, Oishik Raha, Puneet Sharma, Christopher Uff, Geetha Boyapati, Marios Papadopoulos, Siobhan Kearney, Ravindran Visagan, Ellaine Bosetta, Hasan Asif, Adel Helmy, Liliana Chapas, Silvia Tarantino, Karen Caldwell, Mathew Guilfoyle, Smriti Agarwal, Daniel Brown, Sarah Holland, Tamara Tajsic, Clare Fletcher, Aisha Sebyatki, Shungu Ushewokunze, Sarah Ali, John Preston, Carole Chambers, Mohammed Patel, Daniel Holsgrove, Danielle McLaughlan, Tracey Marsden, Francesca Colombo, Kathryn Cawley, Hellen Raffalli, Stephanie Lee, Anil Israni, Rachael Dore, Taya Anderson, Dawn Hennigan, Shelley Mayor, Samantha Glover, Emmanuel Chavredakis, Debbie Brown, Giannis Sokratous, John Williamson, Cathy Stoneley, Andrew Brodbelt, Jibril Osman Farah, Sarah Illingworth, Anastasios Benjamin Konteas, Deborah Davies, Carol Owen, Loretta Kerr, Peter Hall, Rustam Al-Shahi Salman, Laura Forsyth, Steff C Lewis, James JM Loan, Aileen R Neilson, Jacqueline Stephen, Neil Kitchen, Kirsty A Harkness, Peter JA Hutchinson, Conor Mallucci, Julia Wade, Philip M White
Journal: The Lancet Neurology (2024)

<h2>Summary</h2><h3>Background</h3> The highest priority uncertainty for people with symptomatic cerebral cavernous malformation is whether to have medical management and surgery or medical management alone. We conducted a pilot phase randomised controlled trial to assess the feasibility of addressing this uncertainty in a definitive trial. <h3>Methods</h3> The CARE pilot trial was a prospective, randomised, open-label, assessor-blinded, parallel-group trial at neuroscience centres in the UK and Ireland. We aimed to recruit 60 people of any age, sex, and ethnicity who had mental capacity, were resident in the UK or Ireland, and had a symptomatic cerebral cavernous malformation. Computerised, web-based randomisation assigned participants (1:1) to medical management and surgery (neurosurgical resection or stereotactic radiosurgery) or medical management alone, stratified by the neurosurgeon's and participant's consensus about the intended type of surgery before randomisation. Assignment was open to investigators, participants, and carers, but not clinical outcome event adjudicators. Feasibility outcomes included site engagement, recruitment, choice of surgical management, retention, adherence, data quality, clinical outcome event rate, and protocol implementation. The primary clinical outcome was symptomatic intracranial haemorrhage or new persistent or progressive non-haemorrhagic focal neurological deficit due to cerebral cavernous malformation or surgery during at least 6 months of follow-up. We analysed data from all randomly assigned participants according to assigned management. This trial is registered with ISRCTN (ISRCTN41647111) and has been completed. <h3>Findings</h3> Between Sept 27, 2021, and April 28, 2023, 28 (70%) of 40 sites took part, at which investigators screened 511 patients, of whom 322 (63%) were eligible, 202 were approached for recruitment, and 96 had collective uncertainty with their neurosurgeon about whether to have surgery for a symptomatic cerebral cavernous malformation. 72 (22%) of 322 eligible patients were randomly assigned (mean recruitment rate 0·2 [SD 0·25] participants per site per month) at a median of 287 (IQR 67–591) days since the most recent symptomatic presentation. Participants' median age was 50·6 (IQR 38·6–59·2) years, 68 (94%) of 72 participants were adults, 41 (57%) were female, 66 (92%) were White, 56 (78%) had a previous intracranial haemorrhage, and 28 (39%) had a previous epileptic seizure. The intended type of surgery before randomisation was neurosurgical resection for 19 (26%) of 72, stereotactic radiosurgery for 44 (61%), and no preference for nine (13%). Baseline clinical and imaging data were complete for all participants. 36 participants were randomly assigned to medical management and surgery (12 to neurosurgical resection and 24 to stereotactic radiosurgery) and 36 to medical management alone. Three (4%) of 72 participants withdrew, one was lost to follow-up, and one declined face-to-face follow-up, leaving 67 (93%) retained at 6-months' clinical follow-up. 61 (91%) of 67 participants with follow-up adhered to the assigned management strategy. The primary clinical outcome occurred in two (6%) of 33 participants randomly assigned to medical management and surgery (8·0%, 95% CI 2·0–32·1 per year) and in two (6%) of 34 participants randomly assigned to medical management alone (7·5%, 1·9–30·1 per year). Investigators reported no deaths, no serious adverse events, one protocol violation, and 61 protocol deviations. <h3>Interpretation</h3> This pilot phase trial exceeded its recruitment target, but a definitive trial will require extensive international engagement. <h3>Funding</h3> National Institute for Health and Care Research.