The primary objective of the study is to test the effectiveness of bumetanide across the whole spectrum of sensory processing disorders within ASD, ADHD and/or epilepsy. We also want to determine which subgroups (high/low IQ, comorbidities or not)…
ID
Source
Brief title
Condition
- Mental impairment disorders
- Developmental disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study parameters is the Aberrant Behavior Checklist-Irritability
subscale.
Secondary outcome
Secondary study parameters are behavioral and quality of life parameters and
seizure frequency
Background summary
Sensory processing difficulties are extremely prevalent within the pediatric
psychiatric population and transcend classifications of developmental disorders
(such as Autism Spectrum disorder (ASD) and ADHD). They constitute a group of
devastating neurodevelopmental disorders that have no cure at present. It is
estimated that approximately 1 in 100 children display signs and symptoms that
lead to a diagnosis of ASD , making it more common than childhood cancer and
juvenile diabetes together. Individual differences in ASD and ADHD
manifestation are characterized by substantial variability in symptomatology,
severity and comorbidities. Despite this heterogeneity, common treatment
targets are beginning to be elucidated on a biological level, which may
finally bring the urgently needed etiology driven treatments. A promising
example in this respect is the selective chloride transporter NKCC1 antagonist
bumetanide. Bumetanide has been used for decades as a diuretic drug and its
safety has been confirmed. Bumetanide has recently been proposed as a rational
treatment for sensory processing difficulties based on its capacity to
reinstall the inhibitory action of the principal neurotransmitter
gamma-aminobutyric acid (GABA). A first trial has tested bumetanide in a modest
sample (n = 56) of children with ASD showing an decrease in symptom severity
after three months of treatment with bumetanide. In a recent pilot study, we
have confirmed the potential of bumetanide to treat autism core symptomatology.
In addition, we have established a positive effect on brain activity using EEG.
Building on these previous experiences, we now aim to conduct a larger trial to
confirm the efficacy of bumetanide in ASD, ADHD and/or epilepsy and analyze
which types of neurodevelopmental disorders are most responsive to bumetanide
in terms of severity, intellectual functioning and comorbidity. Here, we
propose to conduct a large, multicenter, placebo-controlled randomized trial
testing bumetanide plus usual care treatment versus placebo plus usual care in
172 children with ASD, ADHD and/or epilepsy. With this design, we expect to
confirm effectiveness of bumetanide as cheap, safe and rational treatment
option for an important subset of developmental disorders.
Study objective
The primary objective of the study is to test the effectiveness of bumetanide
across the whole spectrum of sensory processing disorders within ASD, ADHD
and/or epilepsy. We also want to determine which subgroups (high/low IQ,
comorbidities or not) are associated with a favorable treatment response .
Study design
A multicenter (2 centers: UMC Utrecht and Jonx Groningen) double-blind,
randomized, placebo-controlled trial with 91 days bumetanide treatment,
followed by a 28-day washout period. Children with ASD, ADHD and/or epilepsy
are randomly assigned to either bumetanide or placebo, according to a
computer-generated randomization schedule.
Intervention
Patients will be treated (randomly) with bumetanide or placebo, for 91 days,
followed by 28 days of wash-out. Bumetanide or placebo can be used as add-on
treatment in addition to the regular use of permitted concomitant medications.
Patients will be given twice daily a dose between 0.25 and 1.0 mg
bumetanide/placebo (before breakfast and at the end of the afternoon, at least
2.5 hours before bedtime). Bumetanide/placebo is provided in the form of a 0.5
mg tablet and taken orally. The starting dose for children with body weight *
17 kg and < 33 kg is 0.5 mg/day divided over 2 dosages (i.e., 2 x 0.25 mg/day),
and increased to 1.0 mg/day divided over 2 dosages (i.e., 2 x 0.5 mg/day) when
blood electrolytes are normal and no signs of dehydration are present during
the blood and urine control on day 7 of the study. The starting dose of
children with a bodyweight of * 33 kg is 1.0 mg/day divided over 2 dosages
(i.e., 2 x 0.5 mg/day), which is increased to 2.0 mg/day divided over 2 dosages
(i.e., 2 x 1.0 mg/day) when blood electrolytes are normal and no signs of
dehydration are present during the blood and urine control on day 7 of the
study. The treatment period will be followed by a wash-out period of 28 days to
evaluate return of symptomatology and the reversibility of the treatment
effect.
Study burden and risks
The burden and risks associated with participation in this study are
acceptable, while the intervention can greatly improve the quality of life for
patients and caregivers. Bumetanide has been used as a diuretic for decades.
Since the 1970s, the safety and tolerabilityof bumetanide after short and
prolonged treatment has been established, in both children and adults. The main
adverse events are related to the diuretic activity of the molecule which leads
to a decrease in electrolytes; notably mild hypokalemia are frequently
reported. To monitor the diuretic effects, physical examination (8 times in
total), blood testing (6 times in total) and urine test (1 time) will be
performed with negligable and known risks. To prevent hypokaliemia, potassium
suppletion will be administered during the 91 treatment days. The effect of the
treatment will be measured at 3 times by means of (parent)-questionnaires.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
1. Males or females aged *5 years to *15 years;
2. Above clinical cut-off scores on the Sensory Profile and either a clinical ASD or ADHD diagnosis based on DSM-5 (or DSM-IV) or an epilepsy diagnosis;
3. Written informed consent.
Exclusion criteria
1. Total IQ < 55 (WISC) and/or inability to comply with the protocol-specified procedures for the duration of the study, including treatment, blood sampling to control diuretic effects;
2. Presence of a severe medical or genetic disorder other than related to ASD or epilepsy;
3. Serious, unstable illnesses including, gastroenterological, respiratory, cardiovascular (arrhythmias, QT interval lengthening), endocrinologic, immunologic, hematologic disease, dehydration or hypotension, electrolyte disturbances (Na <133 mmol/L, K <3.5 mmol/L or Ca <2.17 mmol/L (<13y) or <2.2 mmol/L (>13y);
4. Renal insufficiency (CKD st2-5; estimated glomerular filtration rate < 90 ml/min/1.73m2), congenital or acquired renal disease with decreased concentration capacity (tubulopathy, diabetes insipidus) and liver insufficiency interfering with excretion or metabolism of bumetanide;
5. Start of behavioural treatmen during studyt;
6. Treatment with psychoactive medications, including antipsychotics and AEDs, except methylphenidate, is allowed albeit on a stable regime in terms of types and dosage from 2 months prior to the study to the end of the study;
7. Treatment with NSAIDS, aminoglycosides, digitals, antihypertensive agents, indomethacin, probenecid, acetazolamide, Lithium, other diuretics (e.g., furosemide, hydrochlorothiazide), drugs known to have a nephrotoxic potential;
8. Documented history of hypersensitivity reaction to sulfonamide derivatives;
9. Body weight <17 kg.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002875-81-NL |
| CCMO | NL58621.041.16 |