This study is a double-blind, placebo controlled, series of N-of-1 trials of individualised stimulant dose on ADHD symptomatology in children with FASD.

The broad aim of this study is to contribute new evidence towards understanding treatment efficacy for ADHD symptoms in FASD.

Specific aims are:

1. To assess the ongoing effectiveness of stimulant medication prescribed for ADHD symptoms in individual children with FASD of clinically prescribed stimulant medication compared to placebo to control ADHD symptoms (using behavioural and cognitive measures) in children with FASD and ADHD using a N-of-1 trial design.
2. To obtain pilot data to examine feasibility and tolerability of the planned N-of-1 trial design in children with FASD and ADHD for future and larger studies that might seek to examine if the different stimulant types are equally effective relative to placebo.
3. To review the multiple N-of-1 data to analyze key individual factors that mediate the effect of stimulants relative to placebo on ADHD symptoms, including underlying child factors (attention skills, cognitive function), sociodemographic factors and other prenatal exposures.

Study Design:

This is a single site, double-blind, placebo controlled, N-of-1 trial of clinically prescribed, individualised stimulant dose on ADHD symptomatology in children with FASD. The N-of-1 trial has four 2-week treatment blocks (each block consisting of 1 week active drug and 1 week placebo). Interventions will include either prescribed stimulant (active drug) or matched placebo capsules, compared in four 2-week treatment blocks (each block consisting of 1 week active drug and 1 week placebo). Participants will be randomized to the sequence of the treatment arms. Randomisation will be in the two-week pairs - so the order of treatment (A) and placebo (P) to be randomly assigned within each two-week cycle.

Secondarily the investigators will collate outcomes across the N-of-1 trials and make use of a 'series' or multiple N-of-1 trial design18, chosen as it is a valid method of trial design for rare clinical disorders where individualized treatments are required. This design can result in robust evidence, assuming standards of methodological practice.1 In an N-of-1 trial, each participant is assured of receiving both the study medication and placebo, and thus learns whether the treatment works specifically for them or not.

Study objectives:

1. Primary objective:

   Test ongoing effectiveness of stimulant medication in individual children with FASD on pharmacotherapy for ADHD symptomatology, using individual N-of-1 trials.

2. Secondary objectives:

Secondary objective 1: To examine feasibility and tolerability of the N-of-1 trial design in children with FASD and ADHD for future, larger studies that might seek to examine if the different stimulant types are equally effective relative to placebo.

Secondary objective 2: Through quantitative analysis of a series of N-of-1 trials,1 explore individual factors that mediate the effect of stimulants relative to placebo on ADHD symptoms, on children with FASD, including underlying attention skills, cognitive function and other child/sociodemographic factors and additional prenatal exposures.

Exploratory objectives: Investigators will review if there is any change in pediatrician patient management post trial.

Study Population:

Children (4-18 years) with FASD and ADHD seen by the Victorian Fetal Alcohol Service (VicFAS), prescribed stimulant medication for ADHD symptoms. The age limit selected was based on the age in which stimulants have been shown to be effective in controlling ADHD symptoms in the general population, and who are seen by the clinical service.

VicFAS assesses 20 children per year at the diagnostic clinic. All participants are currently approached for consent to the already established VicFAS database, which includes full child demographic, clinical and neurodevelopmental information as well as optional consent for future studies. Participants who have consented to this optional inclusion will be re-consented to this study.

A total of 20 participants will be approached for recruitment to the study. This will be a convenience sample of children seen through the VicFAS FASD diagnostic clinic since inception in September 2019 until study completion (n=20).

Each participant will undergo repeated measures. Estimation of the needed number of cross-overs (that is 'sample size' in N-of-1 studies) was based on having at least 80% power (β = 0.20) to detect a 5.9-point reduction. With 36 observations per participant, (18 placebo, 18 active medication) we achieve >80% power (alpha of 0.05 will be used as the cut-off for significance, one-sided hypothesis test).

Inclusion Criteria:

Each patient must meet all of the following criteria to be enrolled in this trial:

• Is between the ages of 4 - 18 years at the time of randomization.
• Meet diagnostic criteria for FASD or at risk of FASD according to the Australian Guide to the diagnosis of FASD.
• Is a patient of VicFAS or Developmental Paediatrics (Monash Health).
• Has a diagnosis of ADHD according to the DMS-IV criteria.
• Be on a stimulant medication for treatment of ADHD symptoms.
• Be on a stimulant medication as a primary treatment for ADHD.
• Be on a stable dose of stimulant medication for at last 1 month prior to the study.
• Provide a signed and dated informed consent form / and has a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant's behalf.
• If seen by VicFAS/Developmental paediatrics between August 2019 - study commencement date), parent/guardian must have provided verbal or written consent to the VicFAS database PICF and selected 'yes' to the optional consent for contact for 'future research'.

Exclusion Criteria:

Exclusion criteria will include any of the following:

• Inability to read or speak sufficient English for either child or parent/guardian to complete assessment tasks.
• Be on a medication for treatment of ADHD symptoms that is a medication other than stimulants as a primary treatment for ADHD.
• Allergy/sensitivity to Starcke 1500 (Maize Starch and Pregelatinised Maize Starch).
• Unable to swallow capsules.
• Intracranial symptoms or pathology such as epilepsy, hydrocephalus, diagnosed traumatic. brain injury or progressive intracranial tumours that may impact cognitive and behavioural function (children with asymptomatic or static lesions will be eligible).
• An abnormal ECG result at the time of screening deemed clinically significant by study physician.
• Presence of a significant comorbid psychiatric or psychological (excluding ADHD, oppositional defiant disorder, conduct disorder and pervasive development disorder/autism spectrum disorder) including depressive disorder, anxiety disorder, psychotic disorder, suicidality, Tic disorder, anorexia or bulimia nervosa
• Has a known hypersensitivity to starch or other compound relevant to placebo/capsules.
• Has had treatment with any other investigational drug within 4 weeks prior to randomisation.
• If the participant is known to be pregnant, they cannot take part in this research project.
• Parent/guardian not consenting to contact with paediatrician or school.
• Is deemed by their treating paediatrician to be medically unsafe for trial participation.
• Child's school unwilling to participate in outcome assessments.

Beginning 3 months following analysis and article publication, the following will be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept Monash Health institutional conditions for access:

• Group level data that underlie the results reported in this article after de-identification (text, tables, figures and appendices)
• Trial protocol, PICF

The order of medications (placebo/active drug) will be masked to the participant, assessors and investigator. At the end of the trial, the order of medications will be unmasked, and compared with the parent and teachers' observations of the child's behaviour.