RecruitingPhase 2NCT06465823

Efficacy of Bumetanide to Improve Cognitive Functions in Down Syndrome

A Phase 2 Double Blind Placebo Controlled Study on the Efficacy of Bumetanide for Cognitive Improvement in Children and Adolescents With Down Syndrome

Sponsor

Stefano Vicari

Enrollment

64 participants

Start Date

Jan 11, 2023

Study Type

INTERVENTIONAL

Conditions

Down Syndrome

Summary

The aim of the study is to evaluate the clinical efficacy of a known diuretic drug, Bumetanide, in terms of improvement of memory and psychological functioning in children and adolescents with Down syndrome (DS), in order to develop therapeutic strategies for cognitive and psychopathology aspects associated with the syndrome. The study also aims to identify possible predictors and biological and genetic markers related to the efficacy of the treatment. Recently, preliminary studies conducted on the animal model of Down syndrome have proven the efficacy of the drug Bumetanide in counteracting some brain anomalies related to communication between nerve cells (synaptic transmission) typical of the syndrome, with the effect of improving memory skills. Behaviour-enhancing effects have also been found in preliminary studies in humans with other neurodevelopmental disorders (e.g., autism spectrum disorders). The drug Bumetanide could therefore be useful in counteracting the biological mechanisms that cause some cognitive deficits associated with Down syndrome. The potential of this therapeutic approach will be tested through a clinical trial in a population of children and adolescent patients with DS, in a randomized placebo-controlled trial with a three-month treatment with Bumetanide. Participants will be randomly assigned to the experimental group that will receive the treatment (Bumetanide) vs the control/comparison group that will receive the placebo. Bumetanide is a diuretic drug that has been widely used in humans in the past with few side effects, is orally active, and is very inexpensive. 64 participants will be recruited.

Eligibility

Min Age: 10 YearsMax Age: 17 Years

Inclusion Criteria4

The presence of a free trisomy 21 documented by karyotyping
Adolescents from 10 to 17 years old (included)
3 4.5 ≥ Mental age ≤ 8.5 (as assessed by Leiter-3 at visit 1 or by assessment with Leiter-3 within 6 months of the first visit (Visit 1)
Informed consent from their parents and assent from child/adolescent

Exclusion Criteria14

The presence of any neurosensory deficits, such as hypoacusis or serious visual impairments;
The presence of epilepsy;
The presence of electrolyte disorders;
The presence of clinically and/or hemodynamically significant congenital heart defects, defined as patients with congenital heart disease who already underwent or are awaiting surgical/percutaneous correction (including palliative cardiac surgery as Glenn and/or Fontan) or who are under current treatment with cardiac medications.
The presence of a hypersensibility known about sulpha drugs;
The presence of contraindications relative to the treatment by Bumetanide;
Patients already treated by diuretics;
Any of the following abnormal laboratory values at screening:
Hemoglobin <10 g/dL
Abnormal liver function defined as any 2 or more of the following: ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST), ≥3 × ULN alanine aminotransferase (ALT), ≥3 × ULN gamma-glutamyl transpeptidase (GGT), ≥3 × ULN alkaline phosphatase (ALP), or ≥2 × ULN total bilirubin
Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT
Estimated glomerular filtration rate ≤80 mL/min/1.73 m2 (calculated by the Schwartz equation)
Plasma HCO3 > 32 i) A 12-lead ECG demonstrating QTc >450 msec at screening; j) Subject's weight less than 25 Kg.
k) Pregnancy as assessed by urine beta HCG

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Interventions

DRUGBumetanide

Patients in the Bumetanide group will be treated for 3 months with a dose of 0.02 mg/kg twice a day, oral administration. It will be labeled (pre-printed and indistinguishable) with the randomization number and site number and will be delivered in separate blocks during the first, second and fourth appointment. The patients will start the treatment with half of the full target dose during the first week: * If the target dose is 0.5mg BID, only the morning dose will be administrated. * If the target dose is 1.0 mg BID the dose will be 0.5 mg BID. * If the target dose is 1.5mg BID, the morning dose will be 1.0 mg, the evening dose will be 0.5 mg. * If the target dose is 2.0 mg BID the dose will be 1.0 mg BID The patient will continue with the full dose starting from Visit 2 after 1 week of dosing.

DRUGPlacebo

Patients in the control (placebo) group will be given placebo for 3 months twice a day, oral administration. The Placebo tablets will be visually indistinguishable from Bumetanide and packaged as Bumetanide. The placebo will be labeled (pre-printed and indistinguishable) with the randomisation number and site number and will be delivered in separate blocks during the first, second and fourth visits.