Clinical trial NCT02807870: Early Interventions in Children With Attention Deficit/Hyperactivity Disorder
Official title: Early Interventions in Children With Attention Deficit/Hyperactivity Disorder: Randomized Controlled Trial Comparing Methylphenidate Parental Training in Treating Preschool Children With Attention Deficit / Hyperactivity Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Attention Deficit Disorder With Hyperactivity
Preschool Child
Keywords: Parental training
Preschool age
Attention Deficit/Hyperactivity Disorder (ADHD)
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
Collaborators: name: Conselho Nacional de Desenvolvimento Científico e Tecnológico
First posted: 2016-06-21
Enrollment: 153
Sex: ALL
Minimum age (years): 47
Maximum age (years): 71
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Introduction: Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent mental disorders in children and is associated with important negative functional outcomes throughout development. The first signs and symptoms become apparent in preschool age. Therefore, early interventions in this population have the potential of limiting the disorder's negative impact and preventing future impairments in affected individuals. The first-choice medication for treating ADHD is methylphenidate, which has evidence of efficacy and safety in preschool children. However, non-evidence based worries and pressure from the media placed parent training as the first-line treatment for ADHD in clinical guidelines. Parent training is a behavioral intervention implemented with the parents, with weekly sessions for 8 weeks, adequate for treating ADHD dysfunctional symptoms and behaviors. However, the level of evidence for this intervention is reduced. Furthermore, the need of trained therapists in the public health system, added to the difficulties on adherence and comprehension from parents, limit its generalization and raise questions regarding its indications. Until now, no study has compared pharmacological treatment with methylphenidate to parent training in preschool children with ADHD regarding their clinical efficacy and cost-effectiveness. Moreover, no study has evaluated the impact of pharmacological intervention and psychotherapy on neurobiological mechanisms of ADHD, which is crucial for determining their impact on neurodevelopment.

Objectives: This is a double-blind randomized clinical trial that aims to evaluate the efficacy, tolerability, and acceptability of treatment with methylphenidate compared to parental training and placebo in preschool children with ADHD.

Methods: This study will be a randomized, double-blind, parallel-group, evaluating two active interventions and placebo control group. One hundred and fifty children aged 3 years and 11 months and 5 years and 11 months, diagnosed with ADHD, will be randomized to receive treatment with methylphenidate and information (50 children), parental training and treatment with placebo medication (50 children) or belong to active control group with educational information for parents and placebo treatment with no treatment (active control, 50 children). The treatment will last eight weeks, the neurobiological outcomes will be assessed before and after treatment and clinical outcomes will be assessed at weeks 0, 5 and 9. After the end of treatment, all participants will be invited to participate in a 3 years' annual follow-up. 50 children with typical development will also be evaluated in relation to neurobiological measures.

Implications: This study proposes an innovative and relevant analysis, which will enable the field to advance the knowledge of biological mechanisms related to ADHD and to treatment response. Also, the study will expand the evidence to guide early prevention strategies and early intervention.

Detailed description: The recruitment of participants will be performed through social media divulgation, on our official website and through contact with preschools in the city of Sao Paulo. The participants that have been selected on the telephonic pre-screening are called for a diagnostic evaluation and an eligibility criteria verification performed by a child and adolescence psychiatrist and neuropsychologists. The psychiatric care and the outcomes evaluation sessions will be conducted by trained professionals, under the principal investigator's supervision.

The children will be randomized using the website randomization.com to one of the three groups: drug treatment with methylphenidate and educational information, parental training and placebo medication, or active control group with educational information and placebo medication. After the eight-week intervention, the participants can receive treatments not previously offered according to a clinical decision.

All selected participants for the clinical trial will be evaluated and accompanied by a child and adolescent psychiatrist before the study and bi-weekly until its completion. Furthermore, a blind evaluator will be responsible for the outcomes measures evaluation.

The clinical evaluator (child and adolescent psychiatrist) and the research assistant responsible for the questionnaires application will be blind towards the modality of treatment that the participant undergoes.

All of the study's evaluation protocol and monitoring is done on the platform Research Electronic Data Capture - REDCap, a software developed by Vanderbilt University - Tennessee, which is hosted in The Clinics Hospital of the University of São Paulo Medical School server. REDCap presents three main functions: a) electronic data collection; b) data management; c) study flow management. This data bank complies with the international policies of data's privacy and security on health area. In addition to the collection and storage structure, validation, auditing and data exporting tools of the system itself are also used.

The efficacy analysis will be made from treatment intention (data from all randomized patients will be included in the analysis). The outcomes (clinical measures of efficacy and tolerability) will be analyzed through mixed effects analyses, with individual models for each outcome. This model assumes that missing data occurs at random and avoids potential biases associated with the analysis only of the individuals who completed the observations or using the strategy to carry the last observation made. The model will include fixed effects for treatment (three levels), time (0, 5 and 9 weeks), time-treatment interaction and randomization effect for the participants. Effect sizes will be calculated by subtracting of the modification of each of the outcomes between the patients in the active groups versus active group control, and between both active treatments, divided by the standard deviation of the entire sample.

Eligibility criteria: Inclusion Criteria:

* Attention deficit hyperactivity disorder DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) diagnosis
* Score above 32 on the Swanson, Nolan, and Pelham-IV scale
* Child is registered in a school or day care center
* Children without the use of stimulants or any psychotropic in the last 30 days

Exclusion Criteria:

* Intelligence quotient \<70
* The presence of clinical condition or history of neurological disorder or head trauma with conscience loss
* The presence of affective and psychotic disorders, as well as autism spectrum disorders.
* The absence of a legal representative with the capacity to understand the study objectives and the instructions related to its participation.

Primary outcomes:
measure: Change in attention deficit and hyperactivity symptoms
timeFrame: Baseline, after 8 weeks (post intervention) and follow-up 1, 2 and 3 years after the end of the intervention
measure: Change in symptom severity
timeFrame: Baseline, after 8 weeks (post intervention) and follow-up 1, 2 and 3 years after the end of the intervention
measure: Change in social and psychiatric functioning
timeFrame: Baseline, after 8 weeks (post intervention) and follow-up 1, 2 and 3 years after the end of the intervention
Secondary outcomes:
measure: Change in executive functions
timeFrame: Baseline, after 8 weeks (post intervention) and follow-up 1, 2 and 3 years after the end of the intervention
measure: Adverse effects of the treatment
timeFrame: Along 8 weeks.
measure: Evaluate ADHD symptoms that may influence treatment response and adherence
timeFrame: Baseline, after 8 weeks (post intervention) and follow-up 1, 2 and 3 years after the end of the intervention
measure: Evaluate Depression symptoms that may influence treatment response and adherence
timeFrame: Baseline, after 8 weeks (post intervention) and follow-up 1, 2 and 3 years after the end of the intervention
measure: Changes in irritability symptoms
timeFrame: Baseline and after 8 weeks (post intervention) and follow-up 1, 2 and 3 years after the end of the intervention
measure: Changes in disruptive behavior symptoms
timeFrame: Baseline, after 8 weeks (post intervention) and follow-up 1, 2 and 3 years after the end of the intervention
Other outcomes:
measure: Changes in Midbrain, black substance, red nucleus, median raphe, third ventricle, thalamus, anterior horn of lateral ventricles, caudate nucleus and lentiform nucleus
timeFrame: Baseline and after 8 weeks (post intervention).
measure: Changes in Expressed Emotion
timeFrame: Baseline and after 8 weeks (post intervention).
measure: Changes in oscillatory neural connectivity
timeFrame: Baseline and after 8 weeks (post-intervention)
measure: Changes in parenting behavior
timeFrame: Baseline and after 8 weeks (post intervention)
measure: Changes in parenting practices
timeFrame: Baseline and after 8 weeks (post intervention)
measure: Changes in parenting practices
timeFrame: Baseline and after 8 weeks (post intervention)
measure: Changes in parenting sense of competence
timeFrame: Baseline and after 8 weeks (post intervention)
Locations:
city: Sao Paulo
country: Brazil
facility: Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
Study officials:
affiliation: University of Sao Paulo Medical School
name: Guilherme V Polanczyk
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sugaya LS, Salum GA, de Sousa Gurgel W, de Morais EM, Del Prette G, Pilatti CD, Dalmaso BB, Leibenluft E, Rohde LA, Polanczyk GV. Efficacy and safety of methylphenidate and behavioural parent training for children aged 3-5 years with attention-deficit hyperactivity disorder: a randomised, double-blind, placebo-controlled, and sham behavioural parent training-controlled trial. Lancet Child Adolesc Health. 2022 Dec;6(12):845-856. doi: 10.1016/S2352-4642(22)00279-6. Epub 2022 Oct 26.