Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors

Pilot open label study confirming the applicability and efficacy of bumetanide as add-on
treatment for behavioural problems and seizures in 2x10 patients with TSC and a history of
behavioural problems between 8 and 15 years of age. After the baseline screening, included
subjects receive bumetanide for 91 days, followed by a 28 days discontinuation phase, after which endpoint monitoring will be repeated to evaluate the persistence of treatment effect. Test battery assessment will take place at baseline, at the end of bumetanide treatment (Day 91) and after the discontinuation phase (Day 119). The primary endpoint of the study is the ABC-I subscale at Day 91. In addition, a number of cognitive and neurophysiological markers as well as measures of seizure control will be tested.

We propose to conduct a pilot study to confirm the efficacy of bumetanide as add-on treatment to reduce irritability and other behavioral symptoms typical in children and adolescents with TSC, with and without mental retardation.

• Pre-treatment and screening

o Screening for eligibility

o Baseline measurements

• Treatment (D0 to D91)

o Blood analysis at D4, D7, D14, D28, D56

o End of treatment outcome measurements D91

• Washout (D91 to D119)

o End of washout outcome measurements D119

The investigational product will consist of bumetanide, which will be provided for 91 days as an add-on treatment, supplementary to the regular use of AEDs or other (allowed) co-medications. Dose reductions to manage side effects will be allowed at any time. Based upon the expected chance of frequent mild to moderate hypokalemia, all subjects will receive standard potassium supplementation during the 91 days of treatment. The treatment period will be followed by a wash-out period to evaluate
return of symptomatology and reversibility of treatment effect.