This study is funded by the National Institute of Health Research (NIHR) - Award 132914, and is sponsored by University College London (UCL). Ethics approval has been granted by the Health Research Authority under reference 310741. The study is registered on the International Trial Registry - no. 40370. This study presents independent research commissioned by the National Institute for Health Research (NIHR). The views and opinions expressed by authors are those of the authors and do not necessarily reflect those of the NHS, the NIHR, MRC, CCF, NETSCC, or the Department of Health.