Methylphenidate to Address Executive Functioning Impairment in Pediatric Patients with Sickle Cell Disease

Sickle cell disease (SCD) is a genetic disorder of hemoglobin that is characterized by early and progressive neurocognitive dysfunction and affects 100,000 individuals in the United States. Children and adolescents with SCD display specific weaknesses in aspects of executive functioning (EF), including attention, working memory, and inhibitory control. These EF deficits are associated with functional consequences, including poor academic performance, difficulties transferring to and remaining in adult healthcare, and poorer health-related quality of life. To address the debilitating consequences of neurocognitive dysfunction in SCD, recent American Society of Hematology cerebrovascular guidelines endorsed the implementation of domain-specific cognitive treatments in patients with SCD. In the general population, stimulant medications are the most effective treatment to improve EF, and the most extensively studied of these medications is methylphenidate (MPH). However, most patients with SCD and impairment in EF are not prescribed stimulant medication, potentially due to decreased access to care, negative parent treatment expectations, or prescribing providers’ hesitancy to utilize stimulant medications. MPH has the potential to significantly improve EF among patients with SCD, but little is known about the safety and acceptability of this use, limiting uptake. The aims of this proposal will address this gap. The specific aims are: 1) to assess the feasibility, acceptability, and adherence to MPH; 2) to measure key neurobehavioral and safety outcomes; and 3) to evaluate decision-making and determinants influencing MPH utilization among parents. We will recruit 30 patients with diagnosed SCD of any genotype who are between the ages of 8.0 and 17.9 years and have EF impairment (based on performance measures or parent-ratings) for an open-label, single-arm study. Patients will receive 0.6 mg/kg (maximum dose, 20 mg) of MPH for 4 weeks. Feasibility and acceptability will be assessed by using established questionnaires and evaluating the ratio of patients enrolled to approached. Medication adherence will be determined through clinician-administered pill counts. Adverse effects will be assessed pre-MPH (in clinic), after the first dose (in clinic), and weekly thereafter (remotely). We will conduct interviews with 12 parents who enrolled (pre- and post-MPH treatment) and 12 parents who declined participation (immediately after declining) to gather qualitative data on parent-decision making and implementation factors of MPH treatment in children/adolescents with SCD. This will be the first study to examine the safety of MPH in patients with SCD beyond a single day. Data collected from this pilot trial will provide the foundation to apply for an R01-funded study to test the effectiveness of MPH treatment in children/adolescents with SCD and implementation strategies to increase uptake (i.e., hybrid effectiveness-implementation trial). More broadly, information gathered from this trial will facilitate future work aimed at testing and implementing pharmacological treatments to address neurocognitive deficits in patients with SCD. Project Number: 1R03HL180786-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Andrew Heitzer | Institution: ST. JUDE CHILDREN'S RESEARCH HOSPITAL, MEMPHIS, TN | Award Amount: $277,500 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZHL1 CSR-Y (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R03HL18078601