Table 1.

Objectives and outcome measures for the trial

	Objectives	Outcome measures	Time point(s)
Stage 1
Primary outcomes	To demonstrate the feasibility of using DTI and iUS* in addition to standard of care (neuronavigation based on preoperative MRI and intraoperative use of 5-ALA) for neurosurgery (at selected UK NHS hospitals).	Operation length. Successful use of DTI neuronavigation and iUS* to achieve maximal safe tumour resection without major neurological deficit. Extent of tumour resection assessed on postoperative MRI scan. Surgical complication and serious adverse events	Hospital discharge and 6 months post-op.
Stage 2
Primary outcomes	To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (neuronavigation based on preoperative MRI scan and intraoperative 5-ALA) improves deterioration free survival (DFS) (where deterioration relates to global health status only).	Composite of the global health status domain of the QLQ-C30 questionnaire, progression free survival (PFS) and overall survival (OS) with an event defined as either deterioration, progression or death.	To be recorded at baseline; 6 weeks post-op., 3 months post-op. and then 3 monthly up to 24 months.
Secondary outcomes	To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (neuronavigation and intraoperative 5-ALA) improves DFS where deterioration relates to physical functioning, social functioning from the QLQ-C30 and motor dysfunction and communication deficit.	Four composites using the respective domain of QLQ-C30 (physical functioning and social functioning) and BN20 (motor dysfunction and communication deficit) combined with PFS and OS.	To be recorded at baseline; 6 weeks post-op., 3 months post-op. and then 3 monthly up to 24 months.
Secondary outcomes	To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (neuronavigation and intraoperative 5-ALA) improves time to deterioration.	Defined similarly to DFS with the exception that progression is excluded as an event (ie, only deterioration or death are considered). There will be five time to deterioration outcomes, one for each of the domains used in the primary and secondary DFS outcomes, used in turn to define deterioration.	To be recorded at 6 weeks post-op., 3 months post-op. and then 3 monthly up to 24 months.
Secondary outcomes	To assess whether additional intraoperative imaging (DTI and IUS*) to standard of care (neuronavigation and intraoperative 5-ALA) improves OS.	OS (time from randomisation to death or trial closure).	To be recorded at 24 months.
Secondary outcomes	To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (neuronavigation and intraoperative 5-ALA) improves PFS.	PFS (time from randomisation to radiological tumour progression on imaging, as agreed in local MDT.	MRI at 6 months post-op., and then 3 monthly up to 24 months or an MRI performed outside protocol if patient is symptomatic.
Secondary outcomes	To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (neuronavigation and intraoperative 5-ALA) improves the extent of tumour resection.	Extent of resection as volume of residual tumour postoperative contrast-enhanced MRI. Extent of resection as percentage of preoperative tumour volume on postoperative contrast-enhanced MRI.	Postoperative review.
Secondary outcomes	To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (neuronavigation and intraoperative 5-ALA) improves the incidence of surgical complications.	Number and type of surgical complications.	To be recorded at 5 days post-op, or discharge date (whichever is soonest); 6 weeks post-op., 3 months post-op. and then 3 monthly up to 24 months.
Secondary outcomes	To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (neuronavigation and intraoperative 5-ALA) improves the number of patients eligible for adjuvant treatment following surgery.	Number of patients eligible for adjuvant treatment.	3 months post-op.
Secondary outcomes	To assess whether additional intraoperative imaging (DTI and iUS*) to standard of care (neuronavigation and intraoperative 5-ALA) improves functional outcome postoperatively.	WHO performance status mini-MoCA (Montreal Version) Barthel Index MRC grading of power in all four limbs.	To be recorded at baseline, 5 days post-op., or discharge date (whichever is soonest); 6 weeks post-op., 3 months post-op. and then 3 monthly up to 24 months. (MRC grading to be assessed at baseline and 5 days post-op., or discharge date only).
Secondary outcomes	Assess the correlation of proxy to participant classification assessment of quality of life.	At a minimum, answers to questions 29 and 30 of the QLQ-C30. Ideally answers will be provided to all of the QLQ-C30 and BN20.	Baseline, 6 weeks post-op., 3 months post-op. and then 3 monthly up to 24 months. Proxy will not complete questionnaires when the participant stops completing them.
Tertiary mechanistic study objectives—on a subset of participants—	To assess the sensitivity and specificity of the anatomico-spatial location of DTI fibre tracts compared with intraoperative direct electrical stimulation/behavioural change without stimulation but related to adjacent white fibre tract in patients undergoing awake surgery, or motor evoked potential changes in patients undergoing surgery.	Sensitivity and specificity calculation using pre-surgery and post-surgery MRI images.	Analysis will be undertaken post-surgery.
Tertiary mechanistic study objectives—on a subset of participants—	To assess the sensitivity and specificity of iUS* to identify the tumour boundary when compared with 5-ALA, navigated biopsies will be taken from tumour boundary tissue planned for resection.	Intraoperative iUS* images and postoperative MRI scans and intraoperative biopsy samples.	Analysis will be undertaken post-surgery when biopsy results are available.

*if NiUS available, it is to be used.

5-ALA, 5-aminolevulinic acid; BN20, Brain Neoplasm 20 question module; DTI, diffusion tensor imaging; iUS, Intraoperative ultrasound; iUS, intraoperative ultrasound; MDT, multidisciplinary team; MoCA, Montreal Cognitive Assessment; MRC, Medical Research Council; NHS, National Health Service; post-op, postoperative; QLQ-C30, Quality of Life Questionaire - Core 30 module.