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Single-case experimental designs for bumetanide across neurodevelopmental disorders: BUDDI protocol.

ABSTRACT: Bumetanide is a selective NKCC1 chloride importer antagonist which is being repurposed as a mechanism-based treatment for neurodevelopmental disorders (NDDs). Due to their specific actions, these kinds of interventions will only be effective in particular subsets of patients. To anticipate stratified application, we recently completed three bumetanide trials each focusing on different stratification strategies with the additional objective of deriving the most optimal endpoints. Here we publish the protocol of the post-trial access combined cohort study to confirm previous effects and stratification strategies in the trial cohorts and in new participants. Participants of the three previous cohorts and a new cohort will be subjected to 6 months bumetanide treatment using multiple baseline Single Case Experimental Designs. The primary outcome is the change, relative to baseline, in a set of patient reported outcome measures focused on direct and indirect effects of sensory processing difficulties. Secondary outcome measures include the conventional questionnaires 'social responsiveness scale', 'repetitive behavior scale', 'sensory profile' and 'aberrant behavior scale'. Resting-state EEG measurements will be performed at several time-points including at Tmax after the first administration. Assessment of cognitive endpoints will be conducted using the novel Emma Tool box, an in-house designed battery of computerized tests to measure neurocognitive functions in children. This study aims to replicate previously shown effects of bumetanide in NDD subpopulations, validate a recently proposed treatment prediction effect methodology and refine endpoint measurements. EudraCT: 2020-002196-35, registered 16 November 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002196-35/NL.

SUBMITTER: Geertjens L

PROVIDER: S-EPMC9260985 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Single-case experimental designs for bumetanide across neurodevelopmental disorders: BUDDI protocol.

Geertjens Lisa L Cristian Gianina G Haspels Eva E Ramautar Jennifer J van der Wilt Gert Jan GJ Verhage Matthijs M Bruining Hilgo H

BMC psychiatry 20220707 1

<h4>Background</h4>Bumetanide is a selective NKCC1 chloride importer antagonist which is being repurposed as a mechanism-based treatment for neurodevelopmental disorders (NDDs). Due to their specific actions, these kinds of interventions will only be effective in particular subsets of patients. To anticipate stratified application, we recently completed three bumetanide trials each focusing on different stratification strategies with the additional objective of deriving the most optimal endpoint ...[more]

PMID: 35799144

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Project description:BackgroundTreatment development for neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) is impeded by heterogeneity in clinical manifestation and underlying etiologies. Symptom traits such as aberrant sensory reactivity are present across NDDs and might reflect common mechanistic pathways. Here, we test the effectiveness of repurposing a drug candidate, bumetanide, on irritable behavior in a cross-disorder neurodevelopmental cohort defined by the presence of sensory reactivity problems.MethodsParticipants, aged 5-15 years and IQ ≥ 55, with ASD, ADHD, and/or epilepsy and proven aberrant sensory reactivity according to deviant Sensory Profile scores were included. Participants were randomly allocated (1:1) to bumetanide (max 1 mg twice daily) or placebo tablets for 91 days followed by a 28-day wash-out period using permuted block design and minimization. Participants, parents, healthcare providers, and outcome assessors were blinded for treatment allocation. Primary outcome was the differences in ABC-irritability at day 91. Secondary outcomes were differences in SRS-2, RBS-R, SP-NL, BRIEF parent, BRIEF teacher at D91. Differences were analyzed in a modified intention-to-treat sample with linear mixed models and side effects in the intention-to-treat population.ResultsA total of 38 participants (10.1 [SD 3.1] years) were enrolled between June 2017 and June 2019 in the Netherlands. Nineteen children were allocated to bumetanide and nineteen to placebo. Five patients discontinued (n = 3 bumetanide). Bumetanide was superior to placebo on the ABC-irritability [mean difference (MD) -4.78, 95%CI: -8.43 to -1.13, p = 0.0125]. No effects were found on secondary endpoints. No wash-out effects were found. Side effects were as expected: hypokalemia (p = 0.046) and increased diuresis (p = 0.020).ConclusionDespite the results being underpowered, this study raises important recommendations for future cross-diagnostic trial designs.

Project description:BackgroundExecutive function, including prospective memory, initiating, planning, and sequencing everyday activities, is frequently affected by acquired brain injury (ABI). Executive dysfunction necessitates the use of compensatory cognitive strategies and, in more severe cases, human support over time. To compensate for the executive dysfunction experienced, growing options for electronic mainstream and assistive technologies may be used by people with ABI and their supporters.ObjectiveWe outline the study protocol for a series of single-case experimental designs (SCEDs) to evaluate the effectiveness of smart home, mobile, and/or wearable technologies in reducing executive function difficulties following ABI.MethodsUp to 10 adults with ABI who experience executive dysfunction and have sufficient cognitive capacity to provide informed consent will be recruited across Victoria and New South Wales, Australia. Other key inclusion criteria are that they have substantial support needs for everyday living and reside in community dwellings. On the basis of the participant's identified goal(s) and target behavior(s), a specific electronic assistive technology will be selected for application. Both identification of the target behavior(s) and selection of the assistive technology will be determined via consultation with each participant (and their key support person, if applicable). The choice of SCED will be individualized for each participant based on the type of technology used in the intervention, the difficulty level of the behavior targeted for change, and the anticipated rate of change. For each SCED, repeated measurements of the target behavior(s) during the baseline condition will provide performance data for comparison with the performance data collected during the intervention condition (with technology introduced). Secondary outcome measures will evaluate the impact of the intervention. The protocol includes 2 customizable Microsoft Excel spreadsheets for electronic record keeping.ResultsRecruitment period is June 2022 through March 2024. Trial results for the individual participants will be graphed and analyzed separately using structured visual analysis supplemented with statistical analysis. Analysis will focus on important features of the data, including both within- and between-phase comparisons for response level, trend, variability, immediacy, consistency, and overlap. An exploratory economic evaluation will determine the impact on formal and informal support usage, together with quality of life, following the implementation of the new technological intervention.ConclusionsThe study has been designed to test the cause-effect functional relationships between the intervention-in this case, electronic assistive technology-and its effect in changing the target behavior(s). The evaluation evidence gained will offer new insights into the application of various electronic assistive technologies for people who experience executive dysfunction following ABI. Furthermore, the results will help increase the capacity of key stakeholders to harness the potential of technology to build independence and reduce the cost of care for this population.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12622000835741, https://www.anzctr.org.au/ACTRN12622000835741.aspx.International registered report identifier (irrid)DERR1-10.2196/48503.

Dataset Information

Single-case experimental designs for bumetanide across neurodevelopmental disorders: BUDDI protocol.

Publications

Single-case experimental designs for bumetanide across neurodevelopmental disorders: BUDDI protocol.

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