Abstract
BackgroundYoung children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA.MethodsThe Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3–7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry.DiscussionFindings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA.Trial registrationClinicalTrials.govNCT04351698. Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020
Highlights
Background and rationale {6a} Sickle cell disease (SCD) is the collective term for a group of autosomal recessive haemoglobinopathies in which haemoglobin polymerises after de-oxygenation, causing red blood cells (RBCs) to become sticky, rigid, and sickle-shaped [1]
SO2 often falls during sleep and results in sleep-disordered breathing (SDB), especially if airway obstruction is related to the size of the adenoids in the nose, the tonsils, and in the throat
Preliminary data from the phase-2 trial show a trend for improved processing speed in children with SCD aged over 8 years randomised to auto-adjusting continuous positive airway pressure (CPAP) [45, 46]. These findings suggest that interventions targeting hypoxic exposure may improve cognitive difficulties for children with SCD
Summary
Background and rationale {6a} Sickle cell disease (SCD) is the collective term for a group of autosomal recessive haemoglobinopathies in which haemoglobin polymerises after de-oxygenation, causing red blood cells (RBCs) to become sticky, rigid, and sickle-shaped [1]. These properties account for the clinical manifestations of SCD, which include anaemia and jaundice [2]. Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils.
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