BACKGROUND: Tuberous sclerosis complex is a genetic disorder leading to 
constitutive activation of mammalian target of rapamycin (mTOR) and growth of 
benign tumours in several organs. In the brain, growth of subependymal giant 
cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, 
requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor 
everolimus substantially and significantly reduced the volume of subependymal 
giant cell astrocytomas. We assessed the efficacy and safety of everolimus in 
patients with subependymal giant cell astrocytomas associated with tuberous 
sclerosis complex.
METHODS: In this double-blind, placebo-controlled, phase 3 trial, patients (aged 
0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, 
the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, 
with an interactive internet-response system, in a 2:1 ratio to oral everolimus 
4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 
ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous 
sclerosis complex and at least one lesion with a diameter of 1 cm or greater, 
and either serial growth of a subependymal giant cell astrocytoma, a new lesion 
of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was 
the proportion of patients with confirmed response--ie, reduction in target 
volume of 50% or greater relative to baseline in subependymal giant cell 
astrocytomas. Analysis was by intention to treat. This study is registered with 
ClinicalTrials.gov, number NCT00789828.
FINDINGS: 117 patients were randomly assigned to everolimus (n=78) or placebo 
(n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in 
the volume of subependymal giant cell astrocytomas versus none in the placebo 
group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel 
test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients 
discontinued treatment because of adverse events. The most common adverse events 
were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the 
placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs 
ten [26%]), and pyrexia (17 [22%] vs six [15%]).
INTERPRETATION: These results support the use of everolimus for subependymal 
giant cell astrocytomas associated with tuberous sclerosis. Additionally, 
everolimus might represent a disease-modifying treatment for other aspects of 
tuberous sclerosis.
FUNDING: Novartis Pharmaceuticals.