Clinical trial NCT06465823: Efficacy of Bumetanide to Improve Cognitive Functions in Down Syndrome
Official title: A Phase 2 Double Blind Placebo Controlled Study on the Efficacy of Bumetanide for Cognitive Improvement in Children and Adolescents With Down Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Down Syndrome
Keywords: Bumetanide, GABA, NKCC1, Memory
Lead sponsor: Bambino Gesù Hospital and Research Institute
Sponsor class: OTHER
Collaborators: name: Italian Institute of Technology (IIT)
First posted: 2024-06-20
Enrollment: 64
Sex: ALL
Minimum age (years): 10
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Principal 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

Principal 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

Primary outcomes:
measure: Visual-Object long-term memory measures
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
Secondary outcomes:
measure: Verbal long-term memory measure
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Visual-Spatial long-term memory measure
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Long-term memory measures : recollection and familiarity
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Long-term memory measure: associative memory
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Long-term measure - child's everyday memory
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Adaptive level
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Executive measure
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Psychopathological measure - semi-structured diagnostic interview
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Psychopathological measure - behavioral and psychopathological aspects
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Psychopathological measure - quantitative scale on anxiety symptoms
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Psychopathological measure - behavioural and emotional problems
timeFrame: Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4
measure: Quality of life
timeFrame: day 1/ day 7± 1/ day 31± 3/day 90 ± 3/day, day 150 ± 4
measure: Quality of sleep
timeFrame: day 1/ day 7± 1/ day 31± 3/day 90 ± 3/day, day 150 ± 4
measure: Bristol stool scale
timeFrame: Day 1, Day 7± 1, Day 31± 3, Day 90 ± 3, Day 150 ± 4
Other outcomes:
measure: Biosample PBMC (blood) for biomarkers
timeFrame: Day 1 and Day 90 ±3
measure: Transcriptomic analysis by RNA-Seq assessment (on PBMCs samples)
timeFrame: Day 1, Day 90 ±3 and Day 150 ±4
measure: Genomic assessment (on blood samples)
timeFrame: Day 1
measure: Proteomic (on plasma and PBMCs samples) assessment
timeFrame: Day 1, Day 90 ± 3 and Day 150 ± 4
measure: Metabolomic (on urine samples) assessment
timeFrame: Day 1, Day 90 ± 3 and Day 150 ± 4
Locations:
city: Rome
country: Italy
facility: Bambino Gesù Children's Hospital
Study officials:
affiliation: Bambino Gesù Children&#39;s Hospital
name: Stefano Vicari
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.