Bumetanide in Autism Medication and Biomarker study

Currently no treatments exist for the core symptoms of Autism Spectrum Disorder
(ASD). Recently an old drug, bumetanide, has been proposed as a novel treatment
for ASD. Bumetanide has been used for decades as a diuretic drug and its safety
has been firmly established also in newborns and children. Bumetanide has a
secondary function; in the brain bumetanide blocks the NKCC1 cation-chloride
co-transporter, and thus decreases internal chloride concentration in neurons.
In turn, this concentration change enhances the inhibitory action of the
neurotransmitter *-aminobutyric acid (GABA) and may thus improve functioning of
brain networks with disturbed chloride homeostasis. Recent pilot study from
our group as well as a first trial in the literature point towards a beneficial
effect of bumetanide on ASD morbidity and confirmed that the drug is safe to
use in children provided that diuretic effects are monitored. If bumetanide
would indeed improve GABAergic signaling and reduce hyperexcitability, then
this treatment is not only expected to improve behavioral symptoms, but also
the notoriously difficult to treat symptoms of sensory overload and cognitive
distraction. In this grant proposal, we aim to perform a placebo-controlled
randomized clinical trial to test efficacy bumetanide on ASD symptomatology and
to derive prognostic biomarkers using cognitive, genetic and EEG assessments
before and after treatment.These studies may lead to a breakthrough in finding
a rational, safe treatment for core features of ASD by repositioning of an
off-patent drug.

The primary objective of the proposed study is to investigate whether
bumetanide therapy indeed reduces autistic symptomatology. Important secondary
goals of this project are to determine whether bumetanide will improve specific
behavioral, neurocognitive, resting state EEG and sensory processing features.

We will conduct a 91 day, double blind, randomized, placebo- controlled trial
with bumetanide followed by a 28 day wash-out period. Eligible patients will be
randomly assigned (1:1) to either bumetanide or placebo according to a
computer-generated randomization schedule using a permuted block design, with
stratification for gender and developmental age. Healthy controls will be
tested on EEG and neurocognitive measurements to generate adequate reference
values for the monitoring of the trial.

Patients will be treated with bumetanide according to a titration period twice
daily or placebo, in the form of syrup, for 91 days followed by a 28-day
washout after each treatment period.
For patients with a body weight of *30 kg: The investigational products consist
of bumetanide or placebo and will be given at a dosage between 0.5mg and 1.0mg
twice a day (before breakfast and at the end of the afternoon, at least 2.5
hours before bedtime) for 91 days. The IP will be administered in the
formulation of a solution (1 mL per intake = 0.5 mg bumetanide or placebo) will
be administered directly into the mouth by means of a graduated dosing syringe.
Starting dosage will be 0.5 mg once a day, then the dose will be escalated to
0.5 mg twice a day on D7, if blood electrolytes are normal and no signs of
dehydration are present after the first checking of blood and urine.
For patients with a body weight of <30 kg: the Bumetanide (0.5 mg/mL solution)
or placebo dose will be calculated on a body weight basis. For these children,
the starting amount will be 0.03 mg/kg divided over 2 dosages per day and
escalated to 0.06mg/day in 2 dosages per day under the same physical conditions
as described above. Parents and patients (as applicable) will be provided with
user instructions to favor the correct and full administration of the IP
solution.

The burden and risks are acceptable while the benefits are expected to be
considerable. Since the 1970s, no serious adverse events were described after
short or prolonged treatment with bumetanide as a diuretic drug in children or
adults. The main adverse events are related to the diuretic activity of the
molecule leading to a decrease in electrolytes, notably hypokalemia are
frequently reported. The burden and risks are acceptable while the benefits are
expected to be considerable. To monitor diuretic effects, physical examination
and blood/urine tests will be performed 8 times with negligible and known
risks. To monitor treatment effect, questionnaires, cognitive testing sessions
and EEG investigations will be conducted 3 times. These tests are generally
well tolerated and are non-invasive .
Bumetanide could be the first pharmacological treatment for the core symptoms
of ASD acting on a key component of the pathophysiology of the disease.
Bumetanide may not only improve behavioral symptoms but may also enhance
cognitive functions and sensory processing. Since these phenomena are
notoriously difficult to treat in ASD, this rational treatment may be very
promising. The symptoms related to ASD and hyperexcitation in particular are
important factors for the inability of patients to fully integrate in society,
the potential benefits are enormous: the treatment is not only relatively safe
and cheap (bumetanide is off-patent), but if successful, will also
substantially reduce the (financial) burden on society. Patients, who otherwise
have no medical treatment option and depend on extensive behavioral treatment
and guidance, could now become integrated in society again. If successful, our
studies may lead to bumetanide to become incorporated in the near future as the
first rational treatment in the clinical guideline for ASD.