Efficacy of Bumetanide to Improve Cognitive Functions in Down Syndrome

NCT ID: NCT06465823

Last Updated: 2024-06-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 64 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-01-11
• Study Completion Date: 2026-09-30

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.

Detailed Description

Down syndrome (DS) is a leading cause of genetically defined intellectual disability. It is characterized by low IQ and cognitive deficits, especially learning and memory. Among the neurobiological causes of these deficits, the increased generation of GABAergic interneurons in the forebrain during development is thought to impair learning and memory in Ts65Dn mice, inducing excessive inhibition and a consequent imbalance of excitatory/inhibitory signals. This derangement would affect cognition in Ts65Dn mice by altering hippocampal synaptic plasticity. Indeed, both LTP and cognitive deficits can be improved by reducing the GABA-mediated signal strength through GABAAR antagonist treatment. Some studies on animal models have helped to demonstrate that the use of an inhibitor of the NKCC1 pump such as Bumetanide helps to restore the imbalance of the GABAergic signal and the synaptic plasticity of the hippocampus with a consequent improvement in memory and learning abilities even after only one treatment week. Recently, the modulation of the GABAergic signal by inhibiting the activity of the NKCC1 pump, a specific inhibitor such as Bumetanide, has demonstrated enormous potential for improving epileptic symptoms and autistic symptoms (disorders associated with an imbalance of the excitatory/inhibitory synaptic signal) in animal models and humans and of memory deficits in DS animal models. The hypothesis of the study is therefore that the use of Bumetanide can counteract the alterations of the cerebral GABAergic signal in people with DS, improving their cognitive and psychological abilities. This is a non-profit phase II randomized placebo-controlled study involving 64 participants. The study for each patient will be concluded at the end of treatment (at 3 months) and follow-up (at 5 months). In general, the study will be concluded with the follow-up visit of the last 64th patient. The enrollment of patients will last one year and will take place, like all the visits foreseen by the trial, only at the IRCCS Bambino Gesù Pediatric Hospital in Rome - Trials Complex Operative Unit. For some biomarker analyses, the study makes use of collaboration with the Italian Institute of Technology and the Giannina Gaslini Institute of Genoa. Participation in the study includes an initial visit to verify that the subject's condition meets the criteria required by the study. Subsequently, six follow-up visits will be scheduled after 1 week, 2 weeks, 1 month, 2 months, 3 months (end of treatment), and 2 months after the end of treatment (after 5 months from the start of treatment). Bumetanide drug and placebo (indistinguishable) will be dispensed to participants during the first (Day 1), second (Day 7± 1), and fourth visit (Day 31± 3). Participants in the Bumetanide group will be treated for three months with a dose of 0.02 mg/kg twice a day orally. Participants in the control group will take a placebo twice a day for three months orally. All participants in the study will undergo instrumental and laboratory tests according to the schedule and times indicated below:

• Psychological and neuropsychological evaluation at the time of recruitment (at the first visit - Day 1), at the end of treatment (after three months - Day 31± 3), and two months after the end of treatment (after five months from the start of treatment - Day 150 ± 4). This evaluation will be carried out through long-term memory tasks, executive functions measures and adaptive level, and through scales and interviews on the psychopathological aspects and will be important for evaluating the effects of the treatment. The first visit includes cognitive level assessment (Day 1).
• Questionnaire on quality of life, sleep, and stool and the analysis of vital signs will be performed at the first visit on Day 1, after one week (Day 7± 1), after one month (Day 31± 3), after three months (Day 90 ± 3) and after two months from the conclusion (five months from the start of treatment - (Day 150 ± 4).
• Physical examination in the first visit (Day 1), after one week (Day 7± 1), after one month (Day 31± 3), after three months (Day 90 ± 3), after two months from the conclusion of the treatment (five months from the beginning of the treatment- Day 150 ± 4).
• Blood sampling, specifically, for the analysis of electrolytes and blood gas and for hemogenic and liver function tests during all visits (Day 1 Day 7± 1, Day 15± 1, Day 31± 3, Day 61± 3, Day 90 ± 3, Day 150 ± 4 ). •Urine analysis at first visit (Day 1 during all visits (Day 1 Day 7± 1, Day 15± 1, Day 31± 3, Day 61± 3, Day 90 ± 3, Day 150 ± 4).
• Audiometric test at the start of treatment (Day 1), after one month (Day 31± 3), after three months (end of treatment - Day 90 ± 3) and two months after the end of treatment (five months after start of treatment - Day 150 ± 4). • Electrocardiogram (ECG) at the first visit (Day 1), after one week (Day 7± 1), after one month (Day 31± 3), after three months (end of treatment - Day 90 ± 3), and two months after the end of treatment (five months after starting treatment - Day 150 ± 4).
• Electroencephalogram (EEG) at the first visit (Day 1), after one month (Day 31± 3) after three months (end of treatment - Day 90 ± 3), and two months after the end of treatment (five months after the start of treatment - Day 150 ± 4).
• Nephrological evaluation at first visit (Day 1), after one week (Day 7± 1), after two weeks (Day 15± 1), after one month (Day 31± 3), after two months and at the end of treatment (after three months - Day 90 ± 3).
• Pregnancy test for girls before starting treatment (Day-1).

The study also predict safety measures. Adverse events will be recorded using the UKU side effect rating scale. Furthermore, participants will be closely monitored by Investigators during critical periods before, during and after the treatment.

Conditions

Down Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Bumetanide

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

Group Type: EXPERIMENTAL

Bumetanide

Intervention Type: 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.

Placebo

Patients in the control group will receive the placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: 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.

Interventions

Bumetanide

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.

Intervention Type: DRUG

Placebo

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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. The presence of a free trisomy 21 documented by karyotyping

2. Adolescents from 10 to 17 years old (included)

3. 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)

4. Informed consent from their parents and assent from child/adolescent

Exclusion Criteria

1. The presence of any neurosensory deficits, such as hypoacusis or serious visual impairments;

2. The presence of epilepsy;

3. The presence of electrolyte disorders;

4. 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.

5. The presence of a hypersensibility known about sulpha drugs;

6. The presence of contraindications relative to the treatment by Bumetanide;

7. Patients already treated by diuretics;

8. 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

• Minimum Eligible Age: 10 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Italian Institute of Technology (IIT)

UNKNOWN

Sponsor Role: collaborator

Stefano Vicari

OTHER

Sponsor Role: lead

Responsible Party

Stefano Vicari

Stefano Vicari - Head of Child and Adolescent Neuropsychiatry Unit

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Stefano Vicari

Role: PRINCIPAL_INVESTIGATOR

Bambino Gesù Children&#39;s Hospital

Locations

Bambino Gesù Children's Hospital

Rome, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Paolo Alfieri

Role: CONTACT

paolo.alfieri@opbg.net

0668592735

Floriana Costanzo

Role: CONTACT

floriana.costanzo@opbg.net

0668597091

Facility Contacts

Stefano Vicari

Role: primary

stefano.vicari@opbg.net

0668592453

Paolo Alfieri

Role: backup

paolo.alfieri@opbg.net

0668591635

References

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.

Reference Type: BACKGROUND

PMID: 17494709 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24904277 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34620512 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23233021 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28485727 (View on PubMed)

Other Identifiers

1042_OPBG_2016

Identifier Type: -

Identifier Source: org_study_id