Bissler 2013.

Methods	Double‐blind, randomised, placebo‐controlled, phase 3 study. Multicentre (24 centres in 11 countries).
Participants	118 participants (aged 18 ‐ 61 years old, 40 males and 78 females) having at least one angiomyolipoma 3 cm or larger in diameter, and a diagnosis of tuberous sclerosis per consensus criteria (Roach 1998, Hyman 2000) were recruited. 79 participants were in the treatment group and 39 participants were in the placebo group. Participants were 18 years or older. 23 participants in the placebo group withdrew, mainly due to disease progression. However, all participants were included in the analysis. There were 2/79 participants in intervention arm and 3/36 participants in the placebo arm with sporadic lymphangioleiomyomatosis (without TSC) which we could not separate from the analysis. For a future version of this review, we plan to contact study authors to obtain more detailed information so that we can analyse outcome from only people with TSC. We also plan to contact study authors to ascertain if the TSC participants meet the latest diagnostic criteria (Northrup 2013).
Interventions	Participants were randomized into either: 1. oral everolimus 10 mg/day, or 2. oral placebo. Median exposure of intervention was 38 weeks for the treatment group and 34 weeks for placebo group. Kidney CT or MRI was carried out at baseline, 12, 24, 48 weeks and annually after start of treatment. Although it was stated that the core phase of the trial lasted until the last randomised participant had been treated for 6 months, there was no clear statement on the exact study duration, especially in view of another statement about a subsequent open‐label phase. Study authors will be contacted for exact information about the timeline of randomisation.
Outcomes	Response rate of everolimus on angiomyolipomas (defined as the number of participants having 50% reduction in tumour size as compared to baseline), seizure frequency, response to skin lesions and adverse events.
Notes	Authors who are employees, stock owners or consultants of the funder (Novartis) were involved in the study design, discussion, research, overseeing of data collection and data analysis and interpretation.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned in a 2:1 fashion to receive either everolimus or placebo, stratified by enzyme‐inducing antiepileptic drug use at randomisation and by the presence of sporadic lymphangio leiomyomatosis. Random sequence was generated using interactive web response system.
Allocation concealment (selection bias)	Unclear risk	Not stated.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants received blinded study treatment until angiomyolipoma progression, occurrence of unacceptable toxicity, or participant withdrawal for any other reason. Double blind (participant, caregiver, investigator, outcomes assessor).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Kidney CT or MRI (same modality used throughout the study for each participant) was assessed by a blinded central radiology review. Adverse effects were monitored via participant‐reported or caregiver‐reported responses as well as investigator assessment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Efficacy analyses were done on all randomised participants, and safety analyses were done on all participants who received at least one dose of the study drug and had at least one post‐baseline assessment. Participants not able to be assessed (either by dropout or other reasons) were considered as non responders.
Selective reporting (reporting bias)	Low risk	All outcomes that were mentioned in 'Methods' were reported in 'Results' section of the study report.
Other bias	Unclear risk	It was noted that the authors who are employees, stock owners or consultants of the funder (Novartis) were involved in the study design, discussion, research, overseeing of data collection and data analysis and interpretation.