Efficacy of Bumetanide to Improve Cognitive Functions in Down Syndrome
NCT Number: NCT06465823
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2
Conditions: Down Syndrome
Interventions: DRUG: Bumetanide|DRUG: Placebo
Sponsor: Stefano Vicari
Collaborators: Italian Institute of Technology (IIT)
Sex: ALL
Age: CHILD
Enrollment: 64
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: TRIPLE (PARTICIPANT, INVESTIGATOR, OUTCOMES_ASSESSOR)|Primary Purpose: TREATMENT
Start Date: 2023-01-11
Completion Date: 2026-09-30
Locations: Bambino Gesù Children's Hospital, Rome, 00165, Italy

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.

Primary Outcome Measures: 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 Outcome Measures: Verbal long-term memory measure, Verbal Learning test (PROMEA, Vicari, 2007) - Efficacy criterion. Test assesses long-term verbal memory skills. The raw learning scores for each immediate recall trial (R_ScoreT1, T2, T3) and the raw score of the deferred recall trial (R_ Score Deferred) will be taken into account., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Visual-Spatial long-term memory measure, Visual-Spatial learning test (PROMEA, Vicari, 2007) - Efficacy criterion. Test assesses long-term spatial memory skills.The raw learning scores for each immediate recall trial (R_ScoreT1, T2, T3) and the raw score of the deferred recall trial (R_ Score Deferred) will be taken into account., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Long-term memory measures : recollection and familiarity, Processing Dissociation Procedure - PDP (Costanzo et al., 2013 - Efficacy criterion. Test assesses recollection and familiarity processes to memory performance..In the Processing Dissociation Procedures (PDP) test, of hits alarms responses (H) and false alarms responses (F) will be considered for both the "Inclusion" and "Exclusion" conditions., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Long-term memory measure: associative memory, Associative Memory (Costanzo et al., 2013) - Efficacy criterion. Test assesses recollection and familiarity processes to memory performance.The total raw scores for the "single item" and "associative item" condition and the learning raw scores for each trial of each condition (T1, T2, T3) will be evaluated., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Long-term measure - child's everyday memory, The Observer Memory Questionnaire-Parent Form (OMQ-PF, Gonzalez et al., 2008) - Likert scale questionnaire, test assesses parental beliefs about their child's everyday memory.For the assessment of everyday memory skills, the raw total score will be considered., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Adaptive level, ABAS II (Adaptive Behavior Assessment System Second Edition, Italian adaptation of Ferri R., Orsini A. e Rea M., Eds., 2014) - Efficacy criterion. Scale to obtain the parent's observations about the youth's behaviour and gives a complete overview of child and adolescent adaptive behaviours., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Executive measure, Behavior Rating Inventory Executive Function Second Edition (BRIEF 2, Gioia et al., 2000) Inventory evaluates everyday behaviors associated with EF in home and educational environments.The standardized scores (T) of Inhibit, Self-Monitor, Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, Task-Monitor,and Organization of Materials scales will be evaluated. Behavioral Regulation Index (BRI), Emotional Regulation Index (ERI), Cognitive Regulation Index (CRI) and Global Executive Composite Score (GEC) also will be assessed., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Psychopathological measure - semi-structured diagnostic interview, K-Sads-Present and Lifetime Version (K-SADS-PL) (Kaufman et al., 2004) - Efficacy criterion. Interview assesses psychopathology according to the DSM-5 criteria.The total raw score related to current symptoms reported by the participant's parents in the interview and the symptom/disease decoding scores related to each diagnostic category will be evaluated., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Psychopathological measure - behavioral and psychopathological aspects, Conners' Parent Rating Scale -. Revised, Long Form (CPRS-R:L - Conners, 1997; Nobile, Alberti, \& Zuddas, 2007) - Efficacy criterion. Questionnaire used parent's observations about the youth's behaviour and gives a complete overview of child and adolescent psychopathological disorders.The T scores of each scale of the questionnaire will also be evaluated., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Psychopathological measure - quantitative scale on anxiety symptoms, Multidimensional Anxiety Scale For Children - (MASC-parent report form March, 1997) - Efficacy criterion. Questionnaire assesses anxiety symptoms.The standardized total score (T) and T scores of the separation anxiety (SP), GAD, social anxiety (SAT), obsessions and compulsions (OC), physical symptoms (PS:T) and harm avoidance (HA) scales will be evaluated., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Psychopathological measure - behavioural and emotional problems, Child Behavior Checklist for Ages 6-18 - CBCL/6-18 (Achenbach e Rescorla, 2001) - Efficacy criterion. Questionnaire assesses behavioural and emotional problems in children and young people aged 6-18 years.The T-scores of each scale of the CBCL 6-18 questionnaire will be evaluated., Change from baseline (day 1) to 3 month (day 90 ± 3), day 150 ± 4|Quality of life, PedsQL (PedsQL, JWVarni, 2004): measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. the raw scores of each scale (Physical , Emotional , Social , School) and the respective mean scores (Physical SC, Emotional Functioning ,Social Functioning , School Functioning), the physical index (T_Physical) , the psychosocial index (T_Psychosocial) and the mean total score (Total Score) of the questionnaire, will be evaluated., day 1/ day 7± 1/ day 31± 3/day 90 ± 3/day, day 150 ± 4|Quality of sleep, Sleep Disorders SDSC (The Sleep Disturbance Scale for Children, Bruni et al., 1996) - Sleepiness inventory is used to obtain the parent's observations about sleep disorders in children in five subdomains.T scores of each scale will be evaluated., day 1/ day 7± 1/ day 31± 3/day 90 ± 3/day, day 150 ± 4|Bristol stool scale, Quality of life Stooling (based on Bristol stool scale) - Diagnostic medical tool designed to classify the form of human faeces into seven categories (Type 1-7), Day 1, Day 7± 1, Day 31± 3, Day 90 ± 3, Day 150 ± 4
Other Outcome Measures: Biosample PBMC (blood) for biomarkers, Exploratory end-point - PBMCs will be analyzed from blood samples of all patients to identify possible biomarkers for response to treatment by evaluating the expression of NKCC1 and other genes (at RNA or protein levels), Day 1 and Day 90 ±3|Transcriptomic analysis by RNA-Seq assessment (on PBMCs samples), Exploratory end-point - All cohort patients will be analyzed for transcriptomic analysis by RNA-Seq. Total mRNA will be purified from PBMC and used for the mRNA-Seq library preparation, Day 1, Day 90 ±3 and Day 150 ±4|Genomic assessment (on blood samples), Exploratory end-point - All participants will be analyzed by whole genome sequencing (both patients who respond to therapy and those who do not show any positive response). Genomic analysis will be performed on the pellet derived from centrifugation of the blood samples collected at visit 1, to obtain the corresponding plasma samples to be used for the proteomic analysis., Day 1|Proteomic (on plasma and PBMCs samples) assessment, Exploratory end-point. Plasma and PBMC samples will be collected from all patients (both patients who respond to therapy and those who do not show any positive response). Five mL of peripheral venous blood samples x (supernatant) will be collected., Day 1, Day 90 ± 3 and Day 150 ± 4|Metabolomic (on urine samples) assessment, Exploratory end-point: Urine samples will be collected from all patients (both patients who respond to therapy and those who do not show any positive response) to identify possible biomarkers for treatment response, Day 1, Day 90 ± 3 and Day 150 ± 4