Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study

Abstract

Objective

The Pediatric Adverse Event Rating Scale (PAERS) measured adverse events of children aged 6–12 years with ADHD and emotional dysregulation in the Micronutrients for ADHD in Youth (MADDY) study, an eight week multi-site randomized clinical trial of a broad-spectrum multinutrient treatment. Treatment sensitivity of the PAERS was assessed by calculating the treatment difference in change of the item scores from baseline to end of the RCT.

Methods

Principal component analysis retained 14 “adverse events” (out of 43 in the PAERS) that reflected ADHD symptoms and emotional dysregulation and was used to group the variables of interest. A combined score ranging from 0 to 5 was created based on symptom presence, functional impairment, and severity. Mean score change was calculated from baseline to week 8 by treatment (multinutrient vs placebo) with intention-to-treat and per-protocol samples. The study has been registered on clinicaltrials.gov as Micronutrients for ADHD in Youth (MADDY) Study, trial registration # NCT03252522 (https://clinicaltrials.gov/ct2/show/NCT03252522).

Results

The 126 children in the ITT sample had a mean age of 9.8 (SD = 1.7), with majority (73%) male, and 72% diagnosed with ADHD prior to the study screening. Baseline presence of PAERS symptoms was similar between treatment groups: the highest proportion was ADHD symptoms, followed by Irritable symptoms. The micronutrient group showed a greater decrease (improvement) in the mean anxiety combined score than the placebo group with a between-group difference in change of −0.36 (95% CI: −0.67, −0.04; p = .03) with ITT data and −0.48 (95% CI: −0.81, −0.15; p = .005) with per-protocol (n = 93) data.

Conclusion

The multinutrient supplement did not result in more adverse events than placebo, suggesting it is a safe intervention. In addition to assessing actual adverse events, the PAERS may be a useful adjunct outcome measure for ADHD behaviors.

Keywords:

• ADHD
• micronutrients
• adverse events
• PAERS

Transparency

Declaration of funding

Funding for the study has come through private donations to the Nutrition and Mental Health Research Fund, managed by the Foundation for Excellence in Mental Health Care (FEMHC), as well as from a direct grant from FEMHC and funding from the Gratis Foundation. Dr. Johnstone was supported by an NIH-NCCIH 5R90AT00892403 through the National University for Natural Medicine. Dr. Johnstone’s work on study inception and design was funded by NIH-NCCIH T32 AT002688, as well as through support from the Department of Child and Adolescent Psychiatry, Oregon Health & Science University and Oregon Clinical & Translational Research, through the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000128. Dr. Gracious’ time in assisting in study development was supported by the Jeffrey Research Fellowship, The OSU Dept. of Psychiatry & Behavioral Health; and Dept. of Behavioral Health & Psychiatry, Nationwide Children’s Hospital. The study was also supported by The Ohio State University Center for Clinical and Translational Science award (National Center for Advancing Translational Sciences, Grant 8UL1TR000090-05) as well as the OSU Department of Human Sciences. The study at the Canadian site is funded by the Nutrition and Mental Health Research Fund, administered by the Calgary Foundation. Dr. Leung’s position is supported by the Emmy Droog (endowed) chair in Complementary and Alternative Healthcare.

Declaration of financial/other relationships

Dr. Arnold has received research funding from Supernus Pharmaceuticals (USA), Roche/Genentech Phanaceuticals (Switzerland), Otsuka Pharmaceuticals (Japan), and YoungLiving Essential Oils (USA) and National Institute of Health (USA, R01 MH 100144), has consulted with Pfizer Parmaceuticals (USA), and been on advisory boards for Otsuka (Japan) and Roche/Genentech (Switzerland). Dr. Gracious has been or is a consultant to: AstraZeneca, Otsuka, and NovoNordisc.

Other authors have no conflicts of interest relevant to this article to disclose.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Dr. Leung conceptualized and designed the study, coordinated and supervised data collection, collected data, carried out the initial data analyses, drafted the initial manuscript, and reviewed and revised the manuscript. Dr. Arnold contributed to conceptualization of the analyses, critically reviewed the manuscript for important intellectual content, and reviewed and revised the manuscript.

Dr. Johnstone conceptualized and designed the study, coordinated and supervised data collection, collected data, consulted on the initial analyses, edited the manuscript for important content, and reviewed and revised the manuscript. Dr. Hatsu contributed to the conceptualized and designed the study, coordinated and supervised data collection, consulted on initial analysis, and reviewed and revised the manuscript for important intellectual content. Dr. Gracious contributed to the conceptualized and designed the study, and reviewed and revised the manuscript for important intellectual content. Ms. Srikanth and Ms. Conrad curated and analyzed data, and reviewed and revised the manuscript. Ms. Tost contributed to study design, coordinated and supervised data collection, collected data, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Acknowledgements

We thank the parents and children of the MADDY study for their involvement and support. We also thank the research assistants who assisted with data collection of the PAERS: Leanna Eiterman (LE), Maddy Stein (MS) and Lisa Robinette (LR) at OSU, and Alisha Bruton (AB) and Hayleigh Ast (HA) at OHSU. We are grateful to Dr. Bonnie Kaplan for arranging funding to the three sites to initiate this research in North America.

Data availability statement

The data that support the findings of this study are available from the corresponding author, BL, upon reasonable request and approval of the research team.