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Table 1 TRON study entry criteria

From: The use of everolimus in the treatment of neurocognitive problems in tuberous sclerosis (TRON): study protocol for a randomised controlled trial

  Inclusion criteria Exclusion criteriaa
1 Definite TSC based on current clinical criteria [29] Prior treatment with an mTOR inhibitor
2 Male or female aged 16–60 years Investigational agent taken <30 days prior to randomisation
3 IQ >60 as determined by using WASI and able to participate in direct neuropsychological tests Surgery in last 2 months
4 A score falling on, or below, the 5th percentile (approximately equivalent to −1.5 SD) in one or more of the primary outcome measures Previous brain neurosurgery, with the exception of sub-ependymal giant cell astrocytoma removal surgery or radiosurgery 5 or more yearsv ago
5 Calculated GFR >60 ml/min/1.73 m2, except in case of renal impairment associated with TSC kidney disease, in which event a calculated GFR should be ≥30 ml/min/1.73 m2 Significant haematological abnormality (i.e., haemoglobin <8 g/dl, platelets <80,000/mm3, absolute neutrophil count <1000/mm3)
6 INR ≤1.5 (anti-coagulation permitted if target INR on stable dose of warfarin or LMW heparin for >2 weeks at time of randomisation) Urine protein/creatinine >0.02 g/mmol, except in case of renal impairment associated with TSC kidney disease, in which case urine protein/creatinine ratio should be >0.1 g/mmol for exclusion
7 Adequate liver function as shown by serum bilirubin ≤1.5 times ULN, ALT and AST ≤2.5 times ULN Serum creatinine >1.5 times ULN, except in cases of renal impairment associated with TSC complication of kidneys, where serum creatinine should be >300 μmol/L for exclusion
8 If sexually active, negative pregnancy test in females at the time of informed consent, contraception for males and pre-menopausal females in the study Uncontrolled hyperlipidaemia (fasting cholesterol >300 mg/dl or >7.75 mmol/L and fasting triglycerides >2.5 times ULN, or diabetes with fasting serum glucose >1.5 times ULN)
9 Seizure-free or stable seizures as defined by no change in type of AEDs in 6 months prior to full recruitment and randomisation at baseline; doses of drugs may have been changed in the 6 months prior to recruitment History of myocardial infarction, angina or stroke related to atherosclerosis, or any other significant cardiac disease, HIV seropositivity, organ transplant, malignancy other than squamous or basal cell skin cancer
10 Hepatitis B surface antigen-negative, hepatitis C antibody-negative Lymphangioleiomyomatosis with FEV1 < 70 % of predicted, or any other restrictive pulmonary disease
11 All patients must be able to communicate well with the investigator, to understand and comply with the requirements of the study, and to understand and sign the written informed consent form Bleeding diathesis or on oral anti-vitamin K medication other than low-dose warfarin
12 Female patients of childbearing potential must be prepared to use two acceptable methods of contraception (e.g., intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom) from the time of screening Pregnancy/lactation
13   Live vaccine required during trial
14   Use of strong inhibitor of CYP3A4
15   Use of strong inducer of CYP3A4, except for anti-epileptic drugs
16   Intercurrent infection at time of randomisation
17   Inability to complete study materials (outcome measures) in English
18   History of significant trauma-related cognitive deficit
19   Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., pancreatic insufficiency)
20   Known sensitivity to everolimus or other rapamycin analogues or to its excipients
21   Inability to attend scheduled visits
  1. Abbreviations: AED anti-epileptic drug; ALT alanine aminotransferase, AST aspartate aminotransferase, CYP3AE cytochrome P450 3AE, FEV 1 forced expiratory volume in 1 second, GFR glomerular filtration rate, INR international normalised ratio, LMW low molecular weight, mTOR mammalian target of rapamycin, TSC tuberous sclerosis complex, ULN upper limit of normal, WASI Wechsler Abbreviated Scale of Intelligence
  2. aPatients meeting any of the exclusion criteria will be excluded from entry into or continuation in the study unless sponsor approval is obtained