Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Design of Two Phase III Studies (SIGN Trials)

Crutel, Véronique; Lambert, Estelle V.; Penelaud, Pierre-François; Severo, Cristina Albarrán; Fuentes, Joaquín Lomba; Rosier, Antoine; Hervás, Amaia; Marret, Stéphane; Oliveira, Guiomar; Parellada, Mara; Kyaga, Simon; Gouttefangeas, Sylvie; Bertrand, Marianne; Ravel, Denis; Falissard, Bruno

doi:10.1007/s10803-020-04709-8

Cited by 20 publications

(22 citation statements)

References 56 publications

(68 reference statements)

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“…Overall, across studies bumetanide has been well tolerated with common, but not severe, adverse effects including hypokalemia, enuresis, decreased appetite, and dehydration. Two phase III studies of bumetanide in ASD are active but not recruiting (Crutel et al, 2020), another randomized double-blind, placebo-controlled trial is active and recruiting (NCT04766177).…”

Section: Glutamatergic and γ-Aminobutyric Acid (Gaba) Modulating Agentsmentioning

confidence: 99%

Decades of Progress in the Psychopharmacology of Autism Spectrum Disorder

Henneberry

Lamy

Dominick

et al. 2021

J Autism Dev Disord

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Recent decades have been marked by a wave drug treatment research in autism spectrum disorder (ASD). This work has resulted in improved ability to treat commonly occurring behavioral challenges associated with ASD including most prominently irritability marked by aggression, self-injurious behavior, and severe tantrums. While treatment of interfering behavior has progressed in our field, there remain several areas of unmet medical need including most prominently a lack of any approved drug therapies for the core, defining symptoms of autism. We outline the progress to date in the field of autism drug treatment while taking a future look forward into how decades of work can inform better future steps in this field.

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Section: Glutamatergic and γ-Aminobutyric Acid (Gaba) Modulating Agentsmentioning

confidence: 99%

Decades of Progress in the Psychopharmacology of Autism Spectrum Disorder

Henneberry

Lamy

Dominick

et al. 2021

J Autism Dev Disord

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“…Bumetanide (loop-diuretic that may enhance GABAergic inhibition) was found to improve repetitive behaviors and overall core symptoms with small-to-medium effect-sizes, but not social-communication difficulties. However, two large phase-III trials ( n = 422 in total) [ 87 ] were negative and prematurely terminated [ 88 ], yet they did not report usable data, and therefore, evidence was downrated due to reporting bias. Other experimental medications were not found efficacious based on current data.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis

et al. 2022

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Background There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD. Methods We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses. Results We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles. Limitations Most of the studies were inadequately powered (sample sizes of 20–80 participants), with short duration (8–13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms. Conclusions Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.

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“…Currently, one Phase III clinical trial is assessing bumetanide efficacy in autism (NCT04766177; Table 3). A recent press release form Servier and Neurochlore announced that two other two Phase III clinical trials assessing bumetanide efficacy in autism [38] were terminated because no sign of effectiveness was observed (Table 3). This failure, which followed successful clinical studies in the Phase II trials, could be due to a combination of several factors: (i) the study used the lowest (suboptimal) dosage (0.5 versus 2 mg twice daily), as assessed in a previous Phase IIb clinical trial (EudraCT 2013-003259-39); (ii) the study was performed in 50 centers distributed in 14 countries around the world (Phase II trials were in single countries and mostly monocentric); (iii) the possible high dropout rate (as assessed in EudraCT 2013-003259-39 and the other Phase II trials), being included in the statistical analysis for efficacy, Cryogenic electron microscopy (cryo-EM): performed on cooled samples to characterize protein or nucleic acid structures.…”

Section: Neurodevelopmental Disordersmentioning

confidence: 99%

“…Notably, the treatment compliance issues bring along serious efficacy limitations for bumetanide. In a current Phase III clinical trial in autistic people (NCT04766177, NCT03715153, NCT03715166), bumetanide is being used at a suboptimal dosage for efficacy, to avoid dropout of patients from the trial [38].…”

Section: Drawbacks Of Bumetanidementioning

confidence: 99%

Pharmacological tools to target NKCC1 in brain disorders

Savardi

Borgogno

Vivo

et al. 2021

Trends in Pharmacological Sciences

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The chloride importer NKCC1 and the chloride exporter KCC2 are key regulators of neuronal chloride concentration. A defective NKCC1/KCC2 expression ratio is associated with several brain disorders. Preclinical/clinical studies have shown that NKCC1 inhibition by the United States FDA-approved diuretic bumetanide is a potential therapeutic strategy in preclinical/clinical studies of multiple neurological conditions. However, bumetanide has poor brain penetration and causes unwanted diuresis by inhibiting NKCC2 in the kidney. To overcome these issues, a growing number of studies have reported more brain-penetrating and/or selective bumetanide prodrugs, analogs, and new molecular entities. Here, we review the evidence for NKCC1 pharmacological inhibition as an effective strategy to manage neurological disorders. We also discuss the advantages and limitations of bumetanide repurposing and the benefits and risks of new NKCC1 inhibitors as therapeutic agents for brain disorders. Neuronal Cl homeostasis: role in brain function and disordersIn neurons, the sodium (Na + )-potassium (K + )-Cltransporter isoform 1 (NKCC1, SLC12A2) and the K + -Cltransporter isoform 2 (KCC2, SLC12A5) [1] are key regulators of intracellular chloride concentration ([Cl -] i ). In the central nervous system (CNS), NKCC1 functions as a Climporter, and is highly expressed in immature neurons during early development [2]. Conversely, KCC2 expression is relatively low in early development (resulting in a high NKCC1/KCC2 ratio), increases during the postnatal period, and is more highly expressed in mature neurons (resulting in a low NKCC1/KCC2 ratio; Box 1). The fine regulation of [Cl -] i by NKCC1 and KCC2 is essential for brain development, including cell proliferation and apoptosis, and neuronal migration and maturation [3]. Moreover, NKCC1 and KCC2 are key for neuronal synaptic plasticity (see Glossary) and for maintaining a proper excitatory/inhibitory balance, which is fundamental for brain functions [3].A defective NKCC1/KCC2 expression ratio is often associated with several neurological and psychiatric disorders [4]. In particular, a large and growing body of literature reporting preclinical and clinical studies has shown that upregulation of NKCC1 and/or downregulation of KCC2 (resulting in an increased NKCC1/KCC2 ratio) underlie neurodevelopmental, insult-induced neurological, and neurodegenerative disorders [4] (Box 1; see Outstanding questions). Restoring neuronal [Cl -] i by inhibiting NKCC1 with bumetanide (an unselective NKCC1 inhibitor) was the first proof of concept for NKCC1 as a valuable target for several neurological conditions in preclinical (animal models) and clinical studies (patients) [5,6] (see Outstanding questions). Bumetanide is an FDAapproved thick ascending loop (TAL) of Henle diuretic, which acts by inhibiting the kidney transporter NKCC2. Due to its potent diuretic effect, bumetanide is currently indicated only to treat edema and swelling caused by congestive heart failure, acute pulmonary congestion, and hepatic an...

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Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Design of Two Phase III Studies (SIGN Trials)

Cited by 20 publications

References 56 publications

Decades of Progress in the Psychopharmacology of Autism Spectrum Disorder

Decades of Progress in the Psychopharmacology of Autism Spectrum Disorder

Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis

Pharmacological tools to target NKCC1 in brain disorders

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