Stummer 2006.

Study characteristics
Methods	Randomised controlled trial. Randomisation: dynamic allocation algorithm at a separate research unit, in which participants were allocated to minimise the imbalance between treatment groups. No permuted block randomisation applied. Treatment allocation was communicated to local investigators first by telephone and additionally by fax. Sample size: initial power calculations estimated 350 participants were required for an 80% power, but to allow premature study termination an interim analysis was scheduled after 270 participants whereby a 20\5 difference in PFS could be identified with a power of 80%.
Participants	Inclusion criteria: aged 18–72 years with suspected (as assessed by study surgeon) newly diagnosed and untreated malignant glioma. Tumours were to have a distinct ring‐like pattern of contrast enhancement with thick irregular walls on MRI and a core area of reduced signal suggestive of tumour necrosis. Exclusion criteria: tumours in the midline, basal ganglia, cerebellum, or brain stem; > 1 contrast‐enhancing lesion; substantial, non‐contrast‐enhancing tumour with areas suggesting low‐grade glioma with malignant transformation; medical reasons precluding MRI; inability to give consent; tumour location that did not enable complete resection; KPS ≤ 60; renal or liver insufficiency; and history of previous systemic malignancy.
Interventions	Intervention: 5‐aminolevulinic acid (20 mg/kg bodyweight; medac, Wedel, Germany) in freshly prepared solutions orally 3 hours (range 2–4) preoperatively. Solutions were prepared by dissolving the contents of a vial (1.5 g) in 50 mL of drinking water. Surgery was done using a modified neurosurgical microscope (OPMI Neuro/NC4 system with fluorescence kit, Carl Zeiss Surgical GmbH, Oberkochen, Germany), which enabled switching from conventional white xenon illumination to violet–blue excitation light. Control: conventional microsurgery with white light. No placebo. For participants assigned white light, the tumour was resected using conventional illumination.
Outcomes	Primary endpoints: complete tumour resection on MRI (< 72 hours postoperation and > 1.5 T) and PFS. Secondary endpoints: RTV, overall survival, type and severity of neurological deficits after surgery, and toxic effects. Follow‐up at 6 weeks then 3 months and subsequently at 3 monthly intervals until 18 months.
Notes	Residual tumour was defined as contrast enhancement with a volume > 0.175 cm3. Progression was defined as the occurrence of a new tumour lesion with a volume > 0.175 cm3, or an increase in RTV > 25%. PFS defined radiologically in the initial trial and by combined measures in the follow‐up paper (radiological criteria as above plus any new tumour or neurological worsening as defined by an NIHSS score increase > 1). Adverse events classified according to the US National Cancer Institute common toxicity criteria (version 1.0). The NIHSS was used to measure postoperative deficits at 2 and 7 days after surgery, radiological progression at 6 weeks, then at 3, 6, 9, 12, 15, and 18 months' postsurgery. Intercentre consistency not presented. The manufacturer of 5‐aminolevulinic acid (medac GmbH) was involved in the trial, and authors received assistance from the sponsor.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Performed independently with a dynamic allocation algorithm.
Allocation concealment (selection bias)	Low risk	Treatment allocation was communicated by telephone and fax.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding of surgeons, participants, or those involved with treatment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Neuropathology and neuroradiological assessments were blinded, which is important for assessing extent of resection. Clinical outcome assessment was not blinded, which would have affected PFS and adverse events.
Incomplete outcome data (attrition bias) All outcomes	High risk	13 participants were excluded for major violations of MRI inclusion criteria. 34 participants were excluded for histological criteria. In total, out of 322 randomly assigned participants, 270 were analysed intention to treat and 251 per protocol.
Selective reporting (reporting bias)	High risk	Full outcome data were not presented for survival, PFS, and adverse events (particularly in the earlier article and less so in the follow‐up paper). For example, Kaplan‐Meier plots with hazard ratio, 95% confidence interval, and log‐rank analyses for the full cohort were not presented for survival, PFS (no hazard ratio with 95% confidence interval), or time to deteriorate in the NIHSS (subgroup only of those with complete resection). Timing and severity of all adverse events were not fully documented (e.g. no data on wound infections or related complications and medical complications such as pulmonary thromboembolism).
Other bias	High risk	Industry involvement. The sponsor was involved in the study. It was emphasised that there was no direct link with data interpretation. In addition, selected authors received remuneration from the sponsor.