Efficacy of Bumetanide to Improve Cognitive Functions in Down Syndrome

NCT06465823 | Recruiting Phase 2 DMC

• 1 other identifier: 1042_OPBG_2016
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Down Syndrome

Keywords

Bumetanide, GABA, NKCC1, Memory

Outcome Measures

Primary Outcomes (1)

• Visual-Object long-term memory measures

  Visual-Object Learning test (PROMEA, Vicari, 2007) - Efficacy criterion. Test assesses long-term visual memory skills.The total raw score of the visual episodic memory trial, the raw learning scores for each immediate recall trial (R\_Score T1, T2, T3) and the raw score of the deferred recall trial (R\_ Score Deferred) will be evaluated.

  Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4

Secondary Outcomes (14)

• Verbal long-term memory measure

  Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4

• Visual-Spatial long-term memory measure

  Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4

• Long-term memory measures : recollection and familiarity

  Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4

• Long-term memory measure: associative memory

  Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4

• Long-term measure - child's everyday memory

  Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4

Other Outcomes (5)

• Biosample PBMC (blood) for biomarkers

  Day 1 and Day 90 ±3

• Transcriptomic analysis by RNA-Seq assessment (on PBMCs samples)

  Day 1, Day 90 ±3 and Day 150 ±4

• Genomic assessment (on blood samples)

  Day 1

Study Arms (2)

Bumetanide

EXPERIMENTAL

Patients in the experimental group will receive the pharmacological treatment with Bumetanide

Drug: Bumetanide

Placebo

PLACEBO COMPARATOR

Patients in the control group will receive the placebo

Drug: Placebo

Interventions

Bumetanide DRUG

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.

Bumetanide

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 10 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• The presence of a free trisomy 21 documented by karyotyping
• Adolescents from 10 to 17 years old (included)
• ≥ 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Stefano Vicari: lead
• Italian Institute of Technology (IIT): collaborator

Study Sites (1)

Bambino Gesù Children's Hospital

Rome, 00165, Italy

RECRUITING

Related Publications (5)

• Cancedda L, Fiumelli H, Chen K, Poo MM. Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo. J Neurosci. 2007 May 9;27(19):5224-35. doi: 10.1523/JNEUROSCI.5169-06.2007.

  PMID: 17494709 BACKGROUND

• Deidda G, Bozarth IF, Cancedda L. Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives. Front Cell Neurosci. 2014 May 22;8:119. doi: 10.3389/fncel.2014.00119. eCollection 2014.

  PMID: 24904277 BACKGROUND

• Savardi A, Borgogno M, De Vivo M, Cancedda L. Pharmacological tools to target NKCC1 in brain disorders. Trends Pharmacol Sci. 2021 Dec;42(12):1009-1034. doi: 10.1016/j.tips.2021.09.005. Epub 2021 Oct 4.

  PMID: 34620512 BACKGROUND

• Lemonnier E, Degrez C, Phelep M, Tyzio R, Josse F, Grandgeorge M, Hadjikhani N, Ben-Ari Y. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry. 2012 Dec 11;2(12):e202. doi: 10.1038/tp.2012.124.

  PMID: 23233021 BACKGROUND

• Lemonnier E, Villeneuve N, Sonie S, Serret S, Rosier A, Roue M, Brosset P, Viellard M, Bernoux D, Rondeau S, Thummler S, Ravel D, Ben-Ari Y. Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl Psychiatry. 2017 May 9;7(5):e1124. doi: 10.1038/tp.2017.101. No abstract available.

  PMID: 28485727 BACKGROUND

MeSH Terms

Conditions

Down Syndrome

Interventions

Bumetanide

Condition Hierarchy (Ancestors)

Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; meta-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds

Study Officials

• Stefano Vicari

  Bambino Gesù Children&#39;s Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Paolo Alfieri

CONTACT

0668592735; paolo.alfieri@opbg.net

Floriana Costanzo

CONTACT

0668597091; floriana.costanzo@opbg.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The responsible for the collection of the assessments or evaluator will remain blind to treatment allocation during the trial and primary analyses. The diuretic actions of Bumetanide may impact the blinding procedure. To reduce this impact, the psychologist evaluator will be separated from the pediatrician who will treat the children, thus ensuring the blindness to the treatment. A supervisor during each assessment session will control for any possible interference with the evaluator's blindness. The randomization schedule will be kept inaccessible to the personnel involved in the study. In cases of serious adverse effects, the envelope will only be opened by the Principal Investigator who will be the only one to know the treatment assignment. The Principal Investigator will ensure that the contents of the envelope are kept in a place inaccessible to others.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Stefano Vicari - Head of Child and Adolescent Neuropsychiatry Unit

Model Details: This is a double-blind placebo-controlled study. The enrolment will include 64 patients. Children and adolescents with DS (aged 10-17) will be assigned to one of the two conditions by an automated process: Bumetanide treatment or control group, by a stratified random sampling based on the mental age (≥ 4.5 age \<5.5 yrs vs ≥5.5 age \< 8.5yrs). Patients in the Bumetanide group will be treated for 3 months with a dose of 0.02 mg/kg twice a day, oral administration. Patients in the control group will be administered a placebo. The randomization will be conducted during the first appointment after the informed consent has been signed, and the inclusion and exclusion criteria have been verified.

Study Record Dates

• First Submitted: May 6, 2024
• First Posted: June 20, 2024
• Study Start: January 11, 2023
• Primary Completion: December 30, 2025
• Study Completion (Estimated): September 30, 2026
• Last Updated: June 20, 2024

Record last verified: 2024-06

Locations

IT (1)