Efficacy and safety of bumetanide oral liquid formulation in children aged from 2 to less than 7 years old with Autism Spectrum Disorder.
A 6-month randomised, double-blind, placebo controlled multicentre parallel group study to evaluate efficacy and safety of bumetanide 0.5mg twice a day followed by an open label active 6-month treatment period with bumetanide (0.5mg twice a day) and a 6 weeks discontinuation period after treatment stop.

Recent studies suggest that GABAergic neurons and circuits may be altered in
ASD. The conversion of GABA-mediated neuronal excitation into inhibition during
maturation of specific neuronal populations has been reported to be altered in
neurodevelopmental diseases such as autism. This lack of *GABA switch* is due
to persistent high level of expression of Na+/K+/2Cl- co-transporter (NKCC1) vs
K-Cl co- transporters (KCC2). This in turn may lead to abnormal cell migration
and differentiation, immature and imbalanced neuronal network development and
thus to clinically diagnosed deficits observed in this pathology.
Levels of intracellular chloride determine the levels of neuronal inhibition
and have been shown to be elevated in immature neurons and being progressively
reduced within neuronal development. These observations suggest that drugs
reducing intracellular chloride levels may be helpful in normalising chloride
levels and thereby restore inhibitory GABAergic function and neuronal network
maturation.
Bumetanide (Burinex®) is a sulfonamide-derived loop diuretic used for the
management in adult patients of oedema associated with congestive heart
failure, hepatic cirrhosis and renal disease including nephropatic syndrome.
Acting centrally as a NKCC1 inhibitor, bumetanide provokes reduction
of intracellular chloride, switching the aberrant excitatory action of GABA
into an inhibitory action.

The primary objective is to demonstrate the superiority of bumetanide (0.5mg
BID) oral liquid formulation compared to placebo in the improvement of ASD core
symptoms after 6 months of treatment in ASD children aged from 2 to less than 7
years old.

This study is divided into the following periods:
1. Run-in period up to 4 weeks between selection (ASSE) and inclusion (week 0)
visits: without Investigational Medicinal Product (IMP) treatment to
evaluate eligibility.
2. Double-blind treatment period of 6 months between inclusion (week 0) and
month 6 (week 26): at inclusion patients will be randomised to one of the
two parallel groups: bumetanide 0.5mg BID or placebo BID- balanced
randomisation (ratio 1:1).
3. Open label active treatment period of 6 months between month 6 (week 26)
and month 12 (week 52): patients randomised in the bumetanide arm during the
double blind period will continue to be treated by bumetanide up to 0.5mg BID
during the whole open label period. Patients randomised in the placebo arm
during the double blind period will receive bumetanide up to 0.5mg BID.
4. Safety follow-up visit (Wend), 6 weeks after treatment discontinuation:
This period is without any IMP and it will be completed at the end of the study

Blood and urine samples, renal echographies, ecgs, specific scales for the
evaluation of the disease

Cfr adverse events of medication and procedures described in information and
consent form.