Medication Optimization for ADHD: MOVA study

Rationale: Attention-Deficit/Hyperactivity Disorder (ADHD) is, with a prevalence of 5.9-7.1%, one of the most common child psychiatric disorders, and is associated with significant impairment in different functional domains. Pharmacological treatment, with methylphenidate (MPH) typically being the first choice, is often indicated and has been proven highly effective. Stepwise titration is currently the most used form of titration of MPH in which treatment starts with a low dose, that is gradually increased until maximum symptom reduction is achieved or unacceptable side effects occur. Stepwise titration of MPH is often challenging because it is difficult to objectively determine whether MPH is sufficiently effective, and at which dose. This is worrisome, because many children might receive unnecessary treatment, or treatment with a suboptimal dose, which reduces the effectiveness and/ or safety of the treatment. Double-blind placebo-controlled titration (PCT) may be a more sensitive and objective method to determine the effectiveness and optimal dose. PCT is frequently used in research, but the method is labor-intensive, which currently withholds most therapists to use it in clinical practice. In this study, we will evaluate if implementation of an easy-to-use version of PCT in clinical practice can optimize MPH titration, compared to stepwise titration.

Objective:
The primary purpose of this study is to investigate whether PCT leads to an optimization of the use of MPH in clinical practice. More specifically, we plan to examine whether:
I) In the PCT group more children with nonresponses, placebo responses and insufficient clinical responses will be identified compared to the stepwise titration group, (these children will be offered a different treatment option, according to clinical guidelines);
II) PCT leads to a more optimal dose, with better symptom reduction, less side effects and decreased functional impairment compared to stepwise titration;
III) The maintenance dose is reached faster and there is a lower number of patient-therapist contacts in the PCT group compared to stepwise titration;
IV) Children, parents’, teachers’ and therapists’ satisfaction about titration is higher in PCT compared to stepwise titration;
V) Certain predictors can be identified for (non-)response to MPH.

Study design:
A Randomized Controlled Trial (RCT) comparing two forms of MPH titration:
I) an easy-to-use version of PCT (n = 70), and II) stepwise titration, as is commonly used in current clinical practice (n = 70).

Study population:
A total of 140 children, aged 6-12 years old, with a clinical diagnosis of ADHD with indication for pharmacological treatment with short-acting MPH.

Intervention:
Both groups will receive a baseline measurement (T1), comprising several questionnaires on behavioral functioning and socio-demographic information, and the KSADS interview on ADHD and comorbid oppositional defiant disorder (ODD). Subsequently, the PCT group will start with a lead-in phase to determine which doses are tolerated, based on side effects. Subsequently, they will receive three to five different doses of MPH (leaving out doses that are not tolerated in the lead-in phase), including a placebo, in three to five different weeks. The order of doses is blinded for parents, child, and therapist. Parents and teacher will fill in questionnaires on symptom severity and side effects through a web application at the start of titration and at the end of each week. At the end of titration, an automatized and validated algorithm will determine whether the child is a non-responder, placebo-responder or responder, and for the latter group will determine the optimal dose with no or acceptable side effects. The stepwise titration group will start on a low dose, and through regular contact with the therapist, the child may be titrated up to higher dose with acceptable side effects, if necessary and possible. For both groups parents, teacher and therapists will evaluate functioning of the child and the titration method by filling in questionnaires after the titration period (7 weeks after the start of titration: T2) and after a six-month follow-up during (T3). During the follow-up period children in the stepwise titration group will receive care as usual. For children in the PCT group care as usual is extended with the use of the questionnaires which are used to determine the effects of MPH in the titration period (SWAN + side effects questionnaire) before every consultation with the therapist.

Main study parameters:
For this study the endpoints for the 2 titration methods are I) the number of children with nonresponses, placebo responses and insufficient clinical responses, II) the number and severity of remaining ADHD and ODD behaviours, side effects, comorbidities (for example: internalising disorders) and social skills scores, III) the duration of the titration period before the maintenance dose is reached and the number of patient-therapist contacts, IV) childrens’, parents’, teachers’ and therapists’ satisfaction about the titration and V) possible predictors for (non-)responders (for example: estimated IQ, socio-demographic parameters, comorbid disorders, number and severity of ADHD symptoms).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
This study has minimal disadvantages for the participants and their parents. Both titration methods are already being used in clinical practice. The difference for participants in the current trial will be random allocation to one of two titration methods and that questionnaires will be filled in through a web application instead of on paper (which is typically seen as an advantage).
Participation will require a limited extra time investment for participants. Both groups will receive three measurements for research purposes (T1, T2, T3). At baseline (T1), this measurement is estimated to take a maximum of 45 minutes for questionnaires and a 15 minute interview. At T2 and T3, the time investment is estimated to be approximately 30 minutes (T2) and 45 minutes (T3). Children will be asked to fill in a short questionnaire at T2 and T3 this will require a time investment of 5-10 minutes.
We specifically choose to study the group of 6-12 year old children because children typically start using medication for treatment of ADHD in this age period and the importance of adequate ADHD treatment early in life, which can significantly reduce the risk for adverse outcomes later in life (Shaw, Hodgkins et al. 2012).

The main hypotheses tested in this study are:

1. In the PCT group less children will continue MPH treatment after titration because of the potential of PCT to detect non- and placebo-responders. The main outcome measure to test this hypothesis is the proportion of children who continue MPH treatment after titration, measured both at T2 and T3, for each treatment condition. The proportion of children who continue treatment is determined by the number of children who are still being prescribed MPH at T2 or T3, divided by the total number of children who entered the trial in the respective treatment. Differences between the two intervention groups in terms of continuing MPH treatment will be analyzed with a chi-square test.

2. Children in the PCT group who continue treatment with MPH, measured both at T2 and T3, will be treated more optimally with MPH: they will show a greater reduction of ADHD and ODD behaviors, have fewer side effects and decreased functional impairment in comparison to children who continue treatment with MPH in the stepwise titration group. ADHD and ODD behaviors are assessed by the Disruptive Behavioral Rating Scale (Oosterlaan, Scheres et al. 2000) and SWAN (Swanson et al. 2005) (at baseline, T2, and T3. Both at T2 and T3, we will compare the reduction in symptoms over time (T2 or T3 minus baseline) between the two treatment groups. Side effects will be represented by the number and severity of side effects, as assessed by the side effect rating scale, and will be compared between the two treatment groups. Functional impairment will be assessed with SSRS at baseline,T2 and T3, and CBCL and TRF at baseline and T3. The results will be analyzed with t-test analyses.

9.2 Secondary study parameters
The secondary hypothesis tested in this study are:

3. The optimal (maintenance) dose is reached quicker in the PCT group and there are less patient-therapist contacts compared to stepwise titration. At T2 and T3, the therapist will report on dose changes, and the currently used dose, in Follow-up questionnaires. The maintenance dose is determined by the therapists in the Follow up questionnaire. We will compare the two treatment groups for mean time needed (in days) to reach the maintenance dose, and the number patient-therapist contacts during the entire titration period (T1 - T3). The results will be analyzed with t-test analyses.

4. Satisfaction with the titration method will be higher for PCT compared with stepwise titration for parents, teachers and therapists. For all informants, an aggregate score for satisfaction will be composed based on the satisfaction questionnaire. This score will be compared between the two treatment groups at T2 and T3 with t-tests. Additionally, results of the satisfaction questionnaires will be evaluated in a qualitative manner. Concerns and suggestions raised by parents, teachers and therapists will be discussed in the research team in order to optimize the use of PCT in clinical practice.

5. We will try to identify possible predictors for (non-) response to MPH. For non-continuous potential predictors, a logistic regression will be performed to investigate if they influence the response to MPH. For continues predictors a regression analysis will be performed.

Baseline, After titration, follow up (6 months post titration)

This study is a Randomized Controlled Trial (RCT) with two treatment conditions for titration of MPH. A total of 140 children with DSM-V ADHD diagnosis and indication for pharmacological treatment with short-acting MPH will be randomly divided into one of the two treatment conditions: I) an easy-to-use version of double-blind placebo-controlled titration (PCT; n = 70) and II) stepwise titration group (n = 70).