A Clinical Trial of Iron Supplementation for Youth With ADHD and Restless Sleep

RestEaze: A Novel Wearable Device and Mobile Application to Improve the Diagnosis and Management of Restless Sleep in Pediatric Patients With Attention Deficit/Hyperactivity Disorder, Phase II

The goal of this clinical trial is to learn if iron supplementation works to restless sleep in youth with ADHD. A second goal is to learn if iron supplementation helps to ease ADHD symptoms. The main questions that this trial aims to answer are:

Does 3 months of iron supplementation treatment improve parent- and youth self-reported sleep difficulties more than placebo? Does 3 months of iron supplementation treatment improve sleep as measured by actigraphy more than placebo? Does 3 months of iron supplementation treatment improve parent-reported and/or objectively measured attention more than placebo?

Researchers will compare over-the-counter iron supplementation treatment to a placebo (a look-alike substance that contains no drug) to see if iron supplementation works to treat sleep difficulties in youth with ADHD.

Participants will:

• Take iron supplements every day for 3 months
• Visit the clinic once before treatment begins and once at the end of treatment to complete tests and rating scales related to sleep and attention
• Wear motion-monitoring leg bands while sleeping for one 2-week period before treatment begins and one 2-week period at the end of treatment

Study Population Seventy youth (n=70) will be recruited for participation in the proposed study. Youth meeting eligibility criteria will be recruited through Kennedy Krieger Institute's Sleep Disorders Clinic and Center for Neuropsychological and Psychological Assessment (CNaP). Recruitment will be accomplished by posting flyers with study information at the clinics, by reviewing medical record information of upcoming patients to determine potential eligibility, and by asking clinicians to discuss the study with their patients who may be eligible and their caregivers.

Study Design A double-blind, placebo-controlled randomized superiority trial design will be used in this study. Seventy participants will be assigned to treatment and control conditions using permuted block randomization, based on sequential enrollment and equal allocation to study conditions. Both the participant and members of the study team involved in data collection or outcomes assessment will be blinded to the participant's treatment assignment. The treatment interval for the study will be 3 months, which has been sufficient in previous studies to allow for treatment effects to be observed. Pre-treatment and post-treatment, the following data will be collected for each participant:

1) a complete iron blood panel; 2) 14 consecutive nights of actigraphy monitoring using the RestEaze device at home; 3) parent- or self-ratings of sleep quality over the same 14 nights on which the device is worn; 4) ratings of ADHD symptoms(ADHD-RS-V5) completed by parent and teacher; 5) ratings of sleep problems completed by parent; and 6) neuropsychological testing of attention.

Study Treatment Iron supplementation. The NatureMade brand of iron supplement will be administered to all participants in the treatment condition to minimize variability in concentration of the active ingredients across brands/preparations of iron supplements. This brand of iron supplement is independently verified by United States Pharmacopeia (USP), which conducts rigorous evaluation and monitoring of dietary supplements to ensure that they contain the necessary ingredients at the dosages that are claimed by the manufacturer. Dosing will be determined for each participant by the study physician based on weight. All NatureMade pills will be over encapsulated by the Johns Hopkins Investigational Drug Service to ensure treatment blinding for patients. At the conclusion of study participation, participants will work with their physician to determine whether iron supplementation should be continued.

Placebo. Placebo pills will be manufactured by the Johns Hopkins Investigational Drug Service to match the appearance of the over encapsulated NatureMade pills. At the conclusion of the study, participants assigned to the placebo condition whose blood ferritin levels remain under 50ng/mL will be offered a free 3-month supply of the NatureMade active iron treatment.

Treatment adherence. To monitor treatment adherence, all pills (iron and placebo) will be provided to participants in MEMS cap smart pill bottles. Each plain bottle will be labeled with the participant's name and directions for use and will have a MEMS cap which records the date and time each time the cap is removed from the bottle. These data will be stored, linked to the participant's ID number, in the smart pill bottle software and then downloaded to a secure local server within Kennedy Krieger Institute. These data will allow for daily monitoring of treatment adherence by study personnel, which will provide the opportunity for study personnel to reach out to the participant to encourage compliance or troubleshoot any problems throughout each child's study participation. Participants will be removed from the study prior to completion if they experience significant adverse effects of the treatment, if they do not adhere to treatment or initiate other confounding treatments, or at the request of the patient/family.

Measurement of Peripheral Iron Concentrations. Peripheral iron concentrations will be obtained as part of routine clinical care pre- and post-iron supplementation. Standard indicators of iron availability and storage will be tested with a fasting complete blood count (CBC), serum iron, serum ferritin, total iron binding capacity (TIBC) and transferrin level.

Study Outcomes Study outcomes are reported in the Outcome Measures section.

Inclusion Criteria:

• clinically diagnosed with ADHD
• have blood ferritin level below 50ng/mL
• have parent- or self-reported restless sleep

Exclusion Criteria:

• presence of any chronic medical or genetic condition that could impact iron metabolism
• presence of moderate to severe Obstructive Sleep Apnea
• having received Iron supplementation treatment within the past 3 months
• having blood ferritin level indicative of anemia that requires immediate treatment