Background
Methods/design
Study design
Research objectives
Primary objective
Secondary objective
Exploratory objective
Sample size determination
Recruitment
Screening for eligibility
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 |
Informed consent
Randomisation and blinding
Treatment
Safety information and clinical management
Most frequently observed AE resulting from study drug | Most frequently observed laboratory abnormalities |
---|---|
Mouth ulcers | Neutropenia |
Rash | Thrombocytopenia |
Infections | Hypercholesterolemia |
Diarrhoea | Hypertriglyceridemia |
Fatigue | Hypophosphatemia |
Headache | |
Anorexia | |
Nausea | |
Vomiting | |
Non-infectious pneumonitis |
Pregnancy
Outcome measures
Name of measure | |
---|---|
Eligibility visit screening measures | Wechsler Abbreviated Scale of Intelligence (four subtests) [17] |
Edinburgh Handedness Inventory [18] | |
Primary outcome measures | Complex Figure test and List Learning test from the BIRT Memory and Information Processing Battery [20] |
Spatial Working Memory and Stockings of Cambridge from the CANTAB [21] | |
Telephone search dual task from the Test of Everyday Attention [22] | |
Secondary outcome measures | Information Processing Battery, spatial span and attentional set-shifting (IDED) from the CANTAB [21] |
Cancellation task and Verbal Fluency from the Controlled Oral Word Association Test [23] | |
Symptom Checklist-90-Revised [24] | |
Quality of Life in Epilepsy [25] | |
Liverpool Seizure Severity Scale [26] | |
Vineland Adaptive Behaviour Scales-II (survey form) [27] | |
Social Responsiveness Scale – Adult version [28] | |
Social Communication Questionnaire [29] | |
National Adult Reading Test [19] |