A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis

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Brief Title

A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis

Official Title

TRON: A Randomised, Double Blind, Placebo-controlled Study of RAD001 (Everolimus) in the Treatment of Neurocognitive Problems in Tuberous Sclerosis

Brief Summary

      This is a single centre, two-arm, individually randomised, Phase II, double- blind,
      placebo-controlled trial of RAD001 (Everolimus) versus placebo in the treatment of
      neurocognitive problems in patients with tuberous sclerosis (TSC). The IMP is a licensed
      medicine in this patient group but for a different target of effect. The current trial is a
      proof of principle study for memory and executive function outcomes.

      Following an eligibility visit, patients will be scheduled for baseline visit and
      randomization. They will then be followed up for 6 months undergoing both safety and
      neurocognitive assessments whilst taking either the placebo or study drug.

      48 patients aged 16 to 60 years with tuberous sclerosis (TSC) who have IQ > 60 and a
      significant deficit in one or more primary outcome measures will be randomly allocated in a
      ratio of 2:1 to either RAD001 (Everolimus) or Placebo.
    


Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

List Learning test (from the BIRT Memory and Information Processing Battery)

Secondary Outcome

 CANTAB - Rapid Visual Information Processing Battery (RVIP)

Condition

Tuberous Sclerosis

Intervention

Placebo

Study Arms / Comparison Groups

 Everolimus (RAD001)
Description:  2x2.5mg daily

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

48

Start Date

June 2012

Completion Date

August 6, 2018

Primary Completion Date

August 6, 2018

Eligibility Criteria

        Inclusion Criteria:

          1. Definite TSC by current clinical criteria (28);

          2. Male or female aged 16 to 60 yrs;

          3. IQ over 60 by Wechsler Abbreviated Scales of Intelligence (WASI) and able to
             participate in direct neuropsychological tests;

          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:

          5. Calculated GFR > 60ml/min/1.73m2 except in case of renal impairment associated with
             TSC complicating kidneys, where a calculated GFR should be ≥30ml/min/1.73m2;

          6. INR 1.5 or less (anticoagulation permitted if target INR on stable dose of warfarin or
             LMW heparin for > 2 weeks at time of randomisation) ;

          7. Adequate liver function as shown by: serum bilirubin less than or equal to 1.5 x ULN,
             ALT and AST less than or equal to 2.5 x ULN;

          8. If sexually active - negative pregnancy test in females at the time of informed
             consent, contraception for males and pre-menopausal females on study);

          9. Seizure free or stable seizures as defined by no change in type of AEDs in 6 months
             prior to full recruitment and randomization at baseline. Doses of drugs may have been
             changed in the 6 months prior to recruitment;

         10. Hepatitis B surface antigen negative, Hepatitis C antibody negative.

         11. All patients must be able to communicate well with the investigator, to understand and
             comply with the requirements of the study, understand and sign the written informed
             consent;

         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, etc.), from the time of screening.

        Exclusion Criteria:

          1. Prior treatment with an mTOR inhibitor;

          2. Investigational agent <30 days prior to randomisation;

          3. Surgery in last 2 months;

          4. Previous brain neurosurgery;

          5. Significant haematological abnormality i.e. haemoglobin < 8g/dL, platelets
             <80,000/mm3, absolute neutrophil count < 1000/mm3);

          6. Urine protein/creatinine >0.02g/mmol except in case of renal impairment associated
             with TSC complication of kidneys, where urine protein/creatinine ratio should be
             >0.1g/mmol for exclusion;

          7. Serum creatinine > 1.5 x ULN except in case of renal impairment associated with TSC
             complication of kidneys, where serum creatinine should be >300µmol/L for exclusion;

          8. Uncontrolled hyperlipidaemia (fasting cholesterol > 300mg/dL or >7.75 mmol/L and
             fasting triglycerides >2.5 x ULN, or diabetes with fasting serum glucose > 1.5 x ULN;

          9. 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. lymphangioleiomyomatosis with FEV1 <70% of predicted, or any other restrictive
             pulmonary disease;

         11. Bleeding diathesis or on oral anti-vitamin K medication other than low dose warfarin;

         12. Pregnancy/lactation;

         13. Live vaccine required during trial;

         14. Use of strong inhibitor of CYP3AE;

         15. Use of strong inducer of CYP3AE 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.
      

Gender

All

Ages

16 Years - 60 Years

Accepts Healthy Volunteers

No

Contacts

Julian Sampson, Prof, , 

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT01954693

Organization ID

SPON803-10

Secondary IDs

2011-004854-25

Responsible Party

Principal Investigator

Study Sponsor

Cardiff University

Collaborators

 Novartis

Study Sponsor

Julian Sampson, Prof, Principal Investigator, Cardiff University


Verification Date

January 2018