title: The use of everolimus in the treatment of neurocognitive problems in tuberous sclerosis (TRON): study protocol for a randomised controlled trial.
abstract: Tuberous sclerosis complex (TSC) is a genetic disorder affecting about 1 in 6000 people and is characterised by the development of tumours in many organs, including the skin and kidneys, and by a range of neurological and neuropsychiatric manifestations. TSC-associated neuropsychiatric disorders (TAND) occur in the majority of those with TSC, and they have a significant impact on patients and their families, given the everyday impact of TAND on education, employment, family and social life. The potential benefits of better treatment for TAND therefore include reduction in health care demands and wider benefits for patients and their carers.
  
  
  
  We have planned a single-centre, two-arm, individually randomised, phase II, double-blind, placebo-controlled trial of everolimus versus placebo in the treatment of neurocognitive problems in patients with tuberous sclerosis. Everolimus is a licensed medicine in this patient group, but for a different target of effect. The present trial is a proof-of-principle study developed to provide effect size estimates which may be used to inform the design of subsequent trials. Forty-eight patients aged 16-60 years with tuberous sclerosis who have an IQ >60 and a significant deficit (at least -2 SD) in one or more primary outcome measures will be randomly allocated in a ratio of 2:1 to receive everolimus or placebo, respectively. Participants will be assessed for eligibility and then be started on study medication 4 weeks later. They will then be randomised and receive placebo or everolimus for 24 weeks. Neurocognitive and safety assessments will be carried out at baseline and weeks 4, 12, 24 and 36.
  
  
  
  This study is designed to determine the effect sizes of treatment with everolimus or placebo for 6 months on specific neurocognitive functions-recall memory (verbal and non-verbal) and executive function-in people affected by TSC who have significant deficits in these functions. These data will provide new evidence to determine whether larger-scale trials are indicated and to explore suitable outcome measures and analytical methods for neurocognitive trial design.
  
  
  
  ISRCTN09739757 . Registered on 28 Dec 2011.
authors: South East Wales Trials Unit, Centre for Trials Research, Cardiff University, 7th floor Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK. randelle@cardiff.ac.uk.
authors: Elizabeth
authors: 0000-0002-1606-3175
authors: E
authors: Randell
authors: South East Wales Trials Unit, Centre for Trials Research, Cardiff University, 7th floor Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK.
authors: Rachel
authors: R
authors: McNamara
authors: Institute of Cancer & Genetics, Cardiff University School of Medicine, Institute of Medical Genetics Building, Heath Park, Cardiff, CF14 4XN, UK.
authors: D Mark
authors: DM
authors: Davies
authors: South East Wales Trials Unit, Centre for Trials Research, Cardiff University, 7th floor Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK.
authors: Eleri
authors: E
authors: Owen-Jones
authors: South East Wales Trials Unit, Centre for Trials Research, Cardiff University, 7th floor Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK.
authors: Nigel
authors: N
authors: Kirby
authors: South East Wales Trials Unit, Centre for Trials Research, Cardiff University, 7th floor Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK.
authors: Lianna
authors: L
authors: Angel
authors: South East Wales Trials Unit, Centre for Trials Research, Cardiff University, 7th floor Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK.
authors: Cheney
authors: C
authors: Drew
authors: South East Wales Trials Unit, Centre for Trials Research, Cardiff University, 7th floor Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK.
authors: Rebecca
authors: R
authors: Cannings-John
authors: Department of Clinical Neuropsychology, Cardiff and Vale University Health Board (University Hospital of Wales), Heath Park, Cardiff, CF14 4XW, UK.
authors: Michelle
authors: M
authors: Smalley
authors: Institute of Cancer & Genetics, Cardiff University School of Medicine, Institute of Medical Genetics Building, Heath Park, Cardiff, CF14 4XN, UK.
authors: Anurag
authors: A
authors: Saxena
authors: School of Psychology, Aras an Phiarsaigh, Trinity College, Dublin 2, County Dublin, Ireland.
authors: Emer
authors: E
authors: McDermott
authors: Institute of Cancer & Genetics, Cardiff University School of Medicine, Institute of Medical Genetics Building, Heath Park, Cardiff, CF14 4XN, UK.
authors: Laura
authors: L
authors: Stockwell
authors: Division of Child & Adolescent Psychiatry, Department of Psychiatry and Mental Health, University of Cape Town, 46 Sawkins Road, Rondebosch, 7700, South Africa.
authors: Petrus J
authors: PJ
authors: de Vries
authors: South East Wales Trials Unit, Centre for Trials Research, Cardiff University, 7th floor Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK.
authors: Kerry
authors: K
authors: Hood
authors: Institute of Cancer & Genetics, Cardiff University School of Medicine, Institute of Medical Genetics Building, Heath Park, Cardiff, CF14 4XN, UK.
authors: Julian R
authors: JR
authors: Sampson
mesh_terms: D000293:Adolescent; D000328:Adult; D002491:Central Nervous System Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002985:Clinical Protocols; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D056344:Executive Function / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D008875:Middle Aged; D019965:Neurocognitive Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D009483:Neuropsychological Tests; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000150:complications* / Q000175:diagnosis / Q000523:psychology; D014852:Wales; D055815:Young Adult
chemical_list: D002491:Central Nervous System Agents; D000068338:Everolimus
keywords: Epilepsy; Everolimus; Neurocognitive; Randomised controlled trial; TSC; Tuberous sclerosis