SUMMARY
Background:
There is insufficient evidence to support treatment recommendations for preschool children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to determine the efficacy and safety of methylphenidate and behavioral parent training (BPT) for preschoolers with ADHD.
Methods:
Eight-week, randomized, double-blind, placebo- and sham BPT- controlled clinical trial including children aged 3-5 years with moderate-severe ADHD. The study was conducted at the Institute of Psychiatry, Hospital das Clinicas, University of SäEo Paulo Medical School. Participants were randomized to receive methylphenidate immediate-release plus sham BPT (Educational intervention, EI) (MPH+EI) (n=51), placebo plus BPT (PLB+BPT) (n=51), or placebo plus EI (PLB+EI) (n=51). Randomization was conducted by an independent research manager using a permuted block randomization procedure. Parents, teachers, study staff and evaluators remained blinded. MPH/PLB were titrated to a maximum dose of 1.25mg/kg/day administered twice daily and BPT/EI were delivered weekly. Primary outcomes were parents and teachers composite score of SNAP-IV scale, the Clinical Global Impressions Severity scale (CGI-S) and the Children’s Global Assessment Scale (CGAS). This trial is registered with clinicaltrials.gov (NCT02807870).
Findings:
Enrollment occurred between August 2016, and October 2019. Among 153 randomized children, 9 discontinued treatment. All participants were included in an intent-to-treat analysis. Children in the MPH+EI vs. PLB+EI group showed greater reductions of SNAP-IV-P/T (endpoint mean difference −3·93; CI95% −7·14, −0·73, ES −0·55 CI95% −0·99, −0·1) and CGI-S scores (endpoint mean difference −0·49; CI95% −0·82, −0·17, ES −0–70 CI95% −1·16, −0·24) and greater increase on CGAS scores (endpoint mean difference 5·25, CI95% 2·09, 8·40, ES 0·8 CI95% 0·32, 1·28). Children in the PLB+BPT vs. PLB+EI group did not show different SNAP-IV-P/T (endpoint mean difference −3·18, CI95% −6·38, 0·02, ES −0·44 CI95% −0·89, 0·003) or CGI-S scores (endpoint mean difference −0·35, CI95% −0·68, −0·03, ES −0·50 CI95% −0·96, −0·04) but showed greater increase on CGAS scores (endpoint mean difference 3·69, CI95% 0·53, 6·85, ES 0·56 CI95% 0·08, 1·04). Children in the MPH+EI vs. PLB+BPT group did not presented statistically or clinically significant differences on primary outcomes. Children in the MPH+EI group had more mild adverse events than the other two groups, and there were no group differences for moderate or severe adverse events.
Interpretation:
This study provides evidence that MPH is effective in reducing ADHD symptoms and improving functionality, and BPT is effective in improving functionality for preschool ADHD during 8 weeks of treatment. The limitations of the study include the duration of the trial and the lack of a combined treatment group. Strengths of the study include the double-blind design and the control for expectancy effects of both medication and BPT.
Funding:
Brazilian National Council for Scientific and Technological Development and São Paulo Research Foundation.
INTRODUCTION
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that typically emerges in early childhood1 and affects approximately 2% of preschool children.2 Preschool ADHD increases the risk for morbidity3 and mortality4, necessitating effective intervention5.
Clinical guidelines recommend behavioral parent training (BPT) as first line treatment followed by stimulants if significant impairment or symptoms remain6. BPT was developed to treat disruptive behaviors7 and is oriented around functional problems and the impairment arising from ADHD. There is evidence that it improves parenting and other outcomes related to ADHD8 but there is uncertainty about its effect on core symptoms because they are commonly reported in randomized controlled trials (RCTs) by parents who are usually unblinded to treatment allocation9,10.
Clinicians prescribe medications like stimulants, alfa-agonists, and antipsychotics more frequently than BPT for this population11,12, despite limited evidence of their efficacy8 and concerns about safety and overuse13,14. National estimates in the US indicate that 76% of children aged 2-5 years in clinical care for ADHD receive medications12. On the other hand, children may go untreated because there is limited access to BPT globally. In the US, only about 55% receive psychological treatment12. Thus, RCTs that evaluate the efficacy and safety of both stimulants and BPT as first line treatment and that include full blinding of both treatments are considered top priority in the field.
The main objective of this study was to determine the efficacy and safety of methylphenidate and BPT in reducing the frequency and severity of ADHD symptoms and improving global functioning in preschool children. Our a priori hypothesis was that methylphenidate would be superior to placebo in reducing core symptoms and BPT would be superior to sham BPT in improving functionality.
METHODS
This eight-week, randomized, double-blind, placebo- and sham BPT- controlled clinical trial was a single-center study conducted at the Institute of Psychiatry, Hospital das Clínicas, University of São Paulo Medical School and approved by its human research ethics committee. Written informed consent was provided by the parent or primary caregiver of each participant. The study protocol is available in appendix (p 37).
Participants
Eligible participants were children aged 3-5 years (47-71 months) recruited by referral of other centers and from the media who met DSM-5 criteria for ADHD15, including the presence of symptoms across different contexts and significant functional impairment. Clinical assessment and diagnosis were performed by child and adolescent psychiatrists experienced in preschool mental health and trained and supervised by the senior investigator (GVP). Diagnosis was based on the semi-structured interview Kiddie Schedule for Affective Disorders and Schizophrenia Lifetime Version (K-SADS-PL)16 following the Research Diagnostic Criteria-Preschool Age (RDC-PA)17, an adaptation for this age-group (appendix p.37). Inter-rater reliability across all six clinicians for all diagnoses was excellent (k>.78).
Inclusion criteria included moderate or severe symptoms i.e., parent ratings ≥32 on the Swanson, Nolan, and Pelham-IV scale (SNAP-IV)18, a scale commonly used in pediatric clinical trials of ADHD, and the child be registered in school or day care center. Exclusion criteria were intelligence quotient (IQ) < 70; affective, psychotic or autism spectrum disorders; use of psychotropic medications during previous 30 days; a major clinical condition (e.g., unstable epilepsy, cardiovascular disease); history of neurological disorder or head trauma with loss of consciousness; or parent/caretaker unable to understand study objectives and instructions.
The Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV)19 was administered by a neuropsychologist. Other measures were collected by trained research assistants to characterize the sample and to investigate secondary outcomes. For details, see the study protocol in appendix (p 37).
Procedures
Methylphenidate
In the methylphenidate (MPH) condition, MPH immediate release was administered orally, twice a day, for 8 weeks. A child and adolescent psychiatrist blinded to treatment condition assessed the children bi-weekly (and whenever parents requested), and titration was performed weekly following a flexible dosing regimen. Recommended doses during the first 4 weeks of treatment were 0·3, 0·5, 0·7, and 0·7 mg/kg/day. From week 5 onwards, doses could be titrated to 1·0 and then up to 1·25 mg/kg/day if there was room for improvement and no limiting adverse effects. Dosage could be decreased at any time due to adverse effects. Residual pills were returned and counted weekly.
Placebo was corn flour only, encapsulated in capsules identical to the MPH in color, size, and weight. Placebo titration was performed following the same procedure.
Behavioral Parent training
Behavioral parent training was conducted according to the Helping the Noncompliant Child (HNC)20 protocol (appendix p 106). HNC has been compared to the New Forest Parenting Package (NFPP), another BPT protocol for the treatment of preschoolers with ADHD, and both were effective according to parent ratings21. The HNC is based on social learning and behavior modification principles and is designed to teach parents how to manage children’s behavior, improve parent-child relationships and parental competencies. It was designed to treat disruptive behaviors and is oriented towards functional problems; it is not directed specifically towards ADHD symptoms. The program consists of 8 weekly individual sessions of 90 minutes each with child and parent together conducted by two psychologists specialized in behavioral therapy. Therapists were trained by a certified trainer of the HNC protocol during two annual workshops and were continuously supervised by a local senior behavioral therapist (GDP).
Educational Intervention
Educational intervention (EI) was used as a sham BPT to control for attention and other nonspecific aspects of BPT and to ensure complete blinding to treatment allocation. The EI protocol was developed by us and focusses on typical development (appendix p 246). It was designed to inform parents about child development, has no active technique included and does not address any aspect of ADHD. The EI follows the same structure as the BPT program i.e., 8 weekly individual sessions of 90 minutes each with both child and parent. Sessions were conducted by two psychologists or learning therapists who had no training in behavioral therapy following the EI protocol and continuously supervised by a senior psychologist.
Randomisation and masking
Eligible participants were randomized into three groups: 1) Methylphenidate plus Educational intervention (MPH+EI); 2) Placebo medication plus Behavioral parent training (PLB+BPT); and 3) Placebo medication plus Educational intervention (PLB+EI). Randomization was conducted by an independent research manager through www.randomization.com using a permuted block randomization procedure with equal allocation and 5 blocks of N=30. Blinding was ensured by rigorous procedures. For full description, see appendix (p 3 and p 37).
Outcome Measures
Children were assessed at baseline and weeks 4 and 8. The first primary outcome was ADHD symptoms measured by the SNAP-IV scale18 which was rated by a blinded independent evaluator based on parental interview (SNAP-IV-P) and completed independently by teachers (SNAP-IV-T) who were also blinded to treatment conditions. For analyses, we computed average-scores across parent and teacher SNAP-IV scores (appendix p 4). Scores for each dimension of symptoms are presented in the appendix (p 9-10), and there was no a priori hypothesis of different effects on dimensions. The second primary outcome was clinical severity measured by the Clinical Global Impressions Severity scale (CGI-S)22 rated by the blinded independent evaluator based on parents’ interview. The third primary outcome was child’s global functioning measured by the Clinical Global Assessment Scale (CGAS)23 and assessed at baseline and week 8 by the blinded psychiatrist who was following the participant throughout the study, thus providing cross-informant validation of outcomes.
Secondary outcomes included an objective cognitive measure, the Conners Kiddie Continuous Performance Test (KCPT-2)24; and questionnaires used to assess irritability and disruptive behaviors, i.e., the Affective Reactivity Index (ARI)25 and the Multidimensional Assessment Profile of Disruptive Behavior, (MAP-DB)26. These clinically relevant symptoms are frequently associated with ADHD, and have been shown to respond to BPT. All secondary outcomes were assessed at baseline and week 8. For detailed description, see appendix (p 5).
Adverse Events
Adverse events were investigated using several strategies: the Barkley’s Side-Effect Rating Scale27 (SERS) and measures of weight, height and BMI assessed weekly; clinical assessments with register of parental spontaneous report and physical examination conducted biweekly; and laboratory exams and electrocardiogram collected at baseline and week 8. For detailed description, see appendix (p 6).
Statistical Analysis
Sample size was calculated for a 0·05 one-sided type I error and 80% power to detect treatment differences in the prespecified primary efficacy endpoint comparisons: MPH+EI vs. PLB+EI and PLB+BPT vs. PLB+EI. Based on prior literature28, we predicted a mean difference between treatment groups of 5.94 SNAP-IV units and a standard deviation of 10·62, yielding an effect size of 0·56 (Cohen’s d). The calculated sample size was 41 in each group. To account for a predicted 20% drop-out rate, we aimed to enroll 150 participants (50 per group).
All participants were included in an intent-to-treat analysis according to randomized treatment assignment. For primary and secondary outcome analyses, we used random intercepts Mixed Effects Models for continuous outcomes. This is an extension of general linear model frequently used in randomized controlled trials which is appropriate for clustered and repeated-measures data. It takes into account the hierarchical structure of the data to deal with within- and between-subjects variance including both fixed and random effects. It uses maximum likelihood estimation to handle missing data assuming missing at random. Independent models included: as fixed effects, time (3 levels: baseline, weeks 4 and 8), group (3 levels: MPH+EI, PLB+BPT, and PLB+EI), time by group interaction, and comorbidity (2 levels: present and absent); and, as random effects, participants (153 levels) and year of data collection (3 levels: 1, 2, and 3). In these models, time was treated as a categorical variable. For adverse events analyses, time was treated as a continuous variable and only participants (153 levels) was entered as a random variable. Time by group interactions for the primary and secondary outcomes and adverse events were explored using least squares means, adjusting for multiple comparisons by the Benjamini and Hochberg method. Post-hoc pairwise comparisons included estimated differences from baseline to endpoint in each group and between-group differences in estimated endpoint scores. Analysis plan is presented in the appendix (p 89)
All analyses were performed in R v.3.5.2 using the package lme4 and lmerTest for conducting Mixed Effects Models. Estimated marginal means were calculated using packages effects and emmeans. Statistical analyses were conducted by an independent investigator (GAS) blinded to the treatment group variable. The trial is registered with clinicaltrials.gov (NCT02807870).
Protocol amendments and deviations
Minor changes of study protocol were made during the study period and are detailed in appendix (p 7 and p 37). These changes are not expected to have any effect on study outcomes.
There were two protocol deviations. First, 47 (30.7%) children did not present with a score ≥ 32 on parent SNAP-IV at the eligibility interview. Second, for 28 (18.3%) participants, different teachers completed the baseline and the outcome assessments. Sensitivity analysis demonstrated no effect of these deviations over the primary outcome, as described in appendix (pp 11–16).
Role of funding source
The funders had no role in study design, collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
RESULTS
Enrollment began in August 2016, and the last participant was randomized in October 2019. One hundred fifty-three children (mean age 60·45 ± 7·6 months) were randomized into the three treatment groups (51 per group). Table 1 summarizes clinical characteristics of the participants. Most were boys (84%) with combined presentation (71%), at least one comorbid disorder (63%), and parents with a high school or college degree (81%). Nine participants discontinued treatment, none because of adverse events (Figure 1). Missing data on outcome assessment is presented in appendix (p 17). One hundred forty-two (92·8%) participants completed at least 7 of 8 possible BPT or EI sessions and 134 (87·5%) received the maximum dose (1·25mg/kg/day) of MPH or PLB, representing a mean absolute dose per day of 26·99 mg (SD 6.15) (appendix pp 18-19).
Table 1.
Baseline Demographic and Clinical Characteristics
| MPH+EI (N=51) | PLB+ BPT (N=51) | PLB+EI (N=51) | Total (N=153) | |
|---|---|---|---|---|
| Child demographics | ||||
| Age, months | 60·06 (7·93) | 60·82 (7·94) | 60·47 (7·03) | 60·45 (7·60) |
| Sex | ||||
| Male | 44 (86%) | 43 (84%) | 41 (80%) | 128 (84%) |
| Female | 7 (14%) | 8 (16%) | 10 (20%) | 25 (16%) |
| IQ child e | 89·24 (11·10) | 90·06 (11·08) | 91·12 (11·44) | 90·14 (11·16) |
| ADHD presentation | ||||
| Inattention | 4 (8%) | 4 (8%) | 3 (6%) | 11 (7%) |
| Hyperactivity / Impulsivity | 12 (24%) | 12 (24%) | 10 (20%) | 34 (22%) |
| Combined | 35 (69%) | 35 (69%) | 38 (75%) | 108 (71%) |
| Number of comorbidities | ||||
| 0 | 15 (29%) | 18 (35%) | 23 (45%) | 56 (37%) |
| 1 | 20 (39%) | 17 (33%) | 18 (35%) | 55 (36%) |
| 2 | 9 (18%) | 9 (18%) | 8 (16%) | 26 (17%) |
| ≥3 | 7 (14%) | 7 (14%) | 2 (4%) | 16 (11%) |
| Comorbidities | ||||
| Oppositional Defiant Disorder | 26 (51%) | 23 (45%) | 17 (33%) | 66 (43%) |
| Conduct Disorder | 9 (18%) | 4 (8%) | 3 (6%) | 16 (11%) |
| Enuresis / Encopresis | 8 (16%) | 6 (12%) | 5 (10%) | 19 (12%) |
| Simple Phobia | 9 (18%) | 12 (24%) | 10 (20%) | 31 (20%) |
| Other Anxiety Disorders | 6 (12%) | 6 (12%) | 3 (6%) | 15 (10%) |
| Other Disorders | 4 (8%) | 5 (10%) | 2 (4%) | 11 (7%) |
| Baseline clinical scores | ||||
| SNAP-IV-P | ||||
| Total a | 38·49 (9·13) | 37·92 (7·95) | 37·78 (6·94) | 38·07 (8·01) |
| Inattention b | 18·16 (4·49) | 17·53 (4·61) | 17·73 (3·95) | 17·80 (4·34) |
| Hyperactivity / Impulsivity b | 20·33 (5·32) | 20·39 (4·83) | 20·06 (3·81) | 20·26 (4·67) |
| SNAP-IV-T f | ||||
| Total a | 35·90 (10·21) | 33·86 (12·13) | 33·86 (10·87) | 34·53 (11·07) |
| Inattention b | 17·29 (6·52) | 16·08 (6·67) | 15·50 (5·59) | 16·28 (6·28) |
| Hyperactivity / Impulsivity b | 18·61 (6·90) | 17·78 (7·41) | 18·36 (6·77) | 18·25 (6·99) |
| SNAP-IV-P/T | ||||
| Total a | 37·38 (7·75) | 35·90 (7·24) | 35·92 (6·60) | 36·40 (7·20) |
| Inattention b | 17·78 (4·32) | 16·76 (4·02) | 16·67 (3·88) | 17·07 (4·08) |
| Hyperactivity / Impulsivity b | 19·60 (4·89) | 19·14 (4·65) | 19·25 (3·79) | 19·33 (4·44) |
| CGI-S c | 4·82 (0·68) | 4·67 (0·77) | 4·65 (0·66) | 4·71 (0·70) |
| CGAS d | 48·82 (7·12) | 49·47 (6·26) | 48·51 (6·39) | 48·93 (6·57) |
| Parent demographics | ||||
| IQ g | 101·96 (11·26) | 106·34 (11·33) | 101·31 (11·77) | 103·18 (11·60) |
| Education (householder) | ||||
| Middle School Incomplete | 7 (14%) | 2 (4%) | 3 (6%) | 12 (8%) |
| Middle School Complete | 8 (16%) | 3 (6%) | 6 (12%) | 17 (11%) |
| High School Complete | 21 (41%) | 25 (49%) | 21 (41%) | 67 (44%) |
| College / Graduation Complete | 15 (29%) | 21 (41%) | 21 (41%) | 57 (37%) |
| Brazilian Criteria SES | 25·60 (7·40) | 30·37 (7·86) | 30·25 (9·05) | 28·76 (8·38) |
Data are mean (SD) or n (%). Abbreviations: ADHD, Attention Deficit and Hyperactivity Disorder; CGAS, Children’s Global Assessment Scale; CGI-S, Clinical Global Impression – Severity scale; MPH+EI, methylphenidate + educational intervention; PLB+BPT, placebo + behavioral parenting training; PLB+EI, placebo + educational intervention; SD, Standard Deviation; SES, Socioeconomic Status; SNAP-IV-P, Swanson, Nolan, and Pelham-IV completed by parents; SNAP-IV-T; Swanson, Nolan, and Pelham-IV completed by teachers; SNAP-IV-P/T, average-scores across parents’ and teachers’ ratings on the Swanson, Nolan, and Pelham-IV.
SNAP total scores range from 0 to 54, with higher scores indicating more severe symptoms.
SNAP Inattention scores and SNAP Hyperactivity-impulsivity scores range from 0 to 27, with higher scores indicating more severe symptoms.
CGI-S scores range from 1 (normal, not at all ill) to 7 (extremely ill).
CGAS scores range from 1-100, with higher scores indicating better global functioning
n=51 MPH+EI; n=50 PLB+BPT; n=51 PLB+EI
n=49 MPH+EI; n=50 PLB+BPT; n=50 PLB+EI
n=51 MPH+EI; n=50 PLB+BPT; n=51 PLB+EI
Figure 1.
Consort Flow Diagram
In primary outcome analyses for ADHD symptoms, time by group interactions were detected for SNAP-IV-P/T score and there were endpoint differences only between MPH+EI vs. PLB+EI (mean difference= −3·93, CI95% −7·14 to −0·73, p-value 0·049, ES = −0·55, CI 95% −0·99, −0·10). (Table 2 and Figure 2). For severity of disorder and global functioning, time by group interactions were detected for CGI-S and CGAS (Table 2 and Figure 2). For the CGI-S score, there was endpoint difference between MPH+EI vs. PLB+EI (mean difference = −0·49, CI95% −0·82 to −0·17, p-value 0Ό0088, ES = −0·70, CI95% −1·16, −0·24). For the CGAS, there were endpoint differences between MPH+EI vs. PLB+EI (mean difference= 5·25, CI95% 2·09 to 8·40, p-value 0·0036, ES = 0·80, CI95% 0·32, 1·28) and between PLB+BPT vs. PLB+EI (mean difference=3·69, CI95% 0·53 to 6·85, p-value 0·033, ES = 0·56, CI95% 0·8, 1·04). There were no differences between MPH+EI vs. PLB+BPT.
Table 2.
Summary of Primary Outcomes Analyses a
| MPH+EI | PLB+BPT | PLB+EI | Time x Group Inter. pc | Results of Pairwise Comparison | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MPH+EI vs. PLB+BPT | MPH+EI vs. PLB+EI | PLB+BPT vs. PLB+EI | |||||||||||||||||
| Base line, mean (SE) | Week 8, mean (SE) | Mean Diff. b (CI) | Baseline, mean (SE) | Week 8, mean (SE) | Mean Diff. b (CI) | Baseline, mean (SE) | Week 8, mean (SE) | Mean Diff. b (CI) | Mean Diff. d (CI) | p | ES e (CI) | Mean Diff. d (CI) | p | ES e (CI) | Mean Diff. d (CI) | p | ES e (CI) | ||
| SNAP-IV-P/T f,g | 37·07 (1·65) | 28·16 (1·66) | 8.90 (6·91, 10·90) | 35·74 (1·65) | 28·92 (1·66) | 6·82 (4·81, 8·83) | 36·08 (1·66) | 32·10 (1·67) | 3·98 (1·97, 5·99) | 0.057 | −0·75 (−3·94, 2·43) | 0·64 | −0·10 (−0·55, 0·34) | −3·93 (−7·14, −0·73) | 0·049 | −0·55 (−0·99, −0·10) | −3·18 (−6·38, 0·02) | 0·077 | −0·44 (−0·89, 0·003) |
| CGI-S i | 4·77 (0·14) | 3·85 (0·14) | 0·92 (0·68, 1·16) | 4·63 (0·14) | 3·99 (0·14) | 0·64 (0·40, 0·89) | 4·63 (0·14) | 4·34 (0·14) | 0·29 (0·05, 0·53) | 0·0099 | −0·14 (−0·47, 0·18) | 0·39 | −0·20 (−0·66, 0·26) | −0·49 (−0·82, −0·17) | 0·0088 | −0·70 (−1·16, −0·24) | −0·35 (−0·68, −0·03) | 0·052 | −0·50, −0·96, −0·04) |
| CGAS j | 48·98 (1·18) | 57·57 (1·19) | −8·59 (−11·16, −6·03) | 49·57 (1·17) | 56·02 (1·20) | −6·44 (−9·02, −3·86) | 48·57 (1·18) | 52·33 (1·22) | −3·76 (−6·36, −1·16) | 0·035 | 1·56 (−1·57, 4·68) | 0·33 | 0·24 (−0·24, 0·71) | 5·25 (2·09, 8·40) | 0·0036 | 0·80 (0·32, 1·28) | 3·69 (0·53, 6·85) | 0·0·033 | 0·56 (0·08, 1·04) |
Abbreviations: CGAS, Children’s Global Assessment Scale; CGI-S, Clinical Global Impression – Severity scale; CI, 95% confidence interval; ES, effect size; Mean Diff, mean difference; MPH+EI, methylphenidate + educational intervention; PLB+BPT, placebo + behavioral parenting training; PLB+EI, placebo + educational intervention; SE, standard error; SNAP-IV-P/T, average-scores across parents’ and teachers’ ratings on the Swanson, Nolan, and Pelham-IV
All participants were included in an intent-to-treat analysis. Descriptive statistics reflect the estimated marginal means from Mixed Effect Models (MEM) analyses. Treatment by time interaction and pairwise comparison results are also based on estimated data from the MEM analyses.
Mean difference between baseline and posttreatment
P value for treatment by time interaction term.
Mean difference between groups in estimated endpoint scores.
Effect sizes were calculated using standardized mean difference (SMD=MD/SD pooled), where MD is the difference between means, and SD pooled is the sample-wide SD at the baseline (SD pooled SNAP-IV-P/T Total = 7.20; SD pooled CGAS = 6.57; SD pooled = CGI-S: 0.70).
SNAP-IV-P/T was computed as the average-scores across parents’ and teachers’ ratings on the Swanson, Nolan, and Pelham-IV.
SNAP-IV-P/T score ranges from 0 to 54, with higher scores indicating more severe symptoms.
CGI-S scores range from 1 (normal, not at all ill) to 7 (extremely ill).
CGAS scores range from 1-100, with higher scores indicating better global functioning
Figure 2.
Changes in Primary Outcomes by Treatment Group and Time
As sensitivity analyses described in appendix (pp 20–22), we investigated SNAP-IV-P and SNAP-IV-T ratings separately. By parent report, there was a time by group interaction for SNAP-IV-P total score and endpoint differences between MPH+EI vs. PLB+EI (mean difference= −5·87, CI95% −9·34 to −2·40, p-value 0·0029, ES = −0·73, CI 95% −1·17, −0·30) and between PLB+BPT vs. PLB+EI (mean difference= −4·21, CI95% −7·68 to −0·75, p-value 0·026, ES = −0·53, CI 95% −0·78, −0·08). By teacher report, there were no significant time by group interactions.
In the secondary outcome analyses, for the KCPT-2, time by group interactions were observed for: detectability, hit reaction time standard deviation (HRT-SD), and commissions, which are indicators of inattentiveness. For detectability and HRT-SD, pairwise comparisons showed significant effect of MPH+EI compared to both PLB+BPT (detectability: mean difference= −5.36, CI95% −8.65, to −2.08, p-value 0.0046, ES = −0·92, CI95% −1·48, −0·36); HRT SD: mean difference= −9·04, CI95% −15·51 to −2·58, p-value 0·016, ES = −0·74, CI95% −1·27, −0·21); and PLB+EI (detectability: mean difference= −4·83, CI95% −8·22 to −1·45, p-value 0·0081, ES = −0·83, CI95% −1·41, −0·25; HRT SD: mean difference= −8·67, CI95% −15·33 to −2·02, p-value 0·016, ES = −0·71, CI95% −1·25, −0·17). No significant endpoint differences between groups were found for commissions, (appendix pp 23–25). For the ARI score, there was a time by group interaction and endpoint differences were observed between PLB+BPT and PLB+EI (mean difference= −1·60, CI95% −2·81 to −0·39, p-value 0·029, ES = −0·50, CI95% −0·88, −0·12) (appendix pp 26–29). For the MAP-DB, time by group interaction was detected only for the Temper Loss dimension, here used as an irritability measure. Significant endpoint differences were observed between MPH+EI vs. PLB+BPT (mean difference= 8·85, CI95% 1·57, 16·13, p-value 0·026, ES = 0·43, CI95% 0·08, 0·77); and PLB+BPT vs. PLB+EI (mean difference= −14·08, CI95% −21·46 to −6·70, p-value 0·0006, ES = −0·68, CI95% −1·03, −0·32) (appendix pp 26–28). Although the time by group interaction for the MAP-DB noncompliance dimension was not significant, there was an endpoint difference between PLB+BPT vs. PLB+EI (mean difference= −12·24, CI95% −20·95 to −3·53, p-value 0·0018, ES = −0·51, CI95% −0·87, −0·15) (appendix pp 26–28).
According to parent spontaneous report, 794 adverse events occurred in 134 (90·5%) children. The number of mild adverse events reported in the MPH+EI group were higher than in the other two groups; there was no difference among groups in the number of moderate or severe adverse events. Ninety-nine (66·9%) children had only mild and 33 (22·3%) children had moderate adverse events. Two children had severe adverse events not related to the study interventions. One child on the MPH+EI group had an asthma attack and was hospitalized and one child was on the PLB+BPT group and was hospitalized due to H1N1 infection. There were no group differences in the number of children with adverse events (Table 3). Decreased appetite and insomnia occurred more frequently in the MPH+EI group than in the other two groups, and increased appetite occurred more frequently in PLB+BPT and PLB+EI groups than in MPH+EI (appendix pp 28–33).
Table 3.
Summary of Adverse Events
| MPH+EI | PLB+BPT | PLB+EI | Total | p a | |
|---|---|---|---|---|---|
| Adverse events reported by parents during clinical evaluations | |||||
| Number of adverse events, No. | |||||
| Mild adverse events b | 332 | 235 | 227 | 794 | <0·0001 n |
| Moderate adverse event c | 15 | 22 | 14 | 51 | 0·23 |
| Severe adverse event d | 1 | 1 | 0 | 2 | 0·77 |
| Number of children with adverse events g | |||||
| No adverse event | 4 (8%) | 6 (12%) | 4 (8%) | 14 (10%) | 0·68 |
| Only mild adverse events b | 36 (71%) | 28 (57%) | 35 (73%) | 99 (67%) | |
| At least 1 Moderate adverse event c | 10 (20%) | 14 (29%) | 9 (19%) | 33 (22%) | |
| At least 1 Severe adverse event d | 1 (2%) | 1 (2%) | 0 | 2 (1%) | |
| Barkley’s Side-Effect Rating Scale (SERS) | |||||
| SERS total score at week 8 e h | 19·11 (14·89) | 14·91 (16·65) | 16·62 (15·43) | 16·87 (15·67) | 0·43 |
| SERS - Number of children with severe adverse events (score ≥7) f, i | |||||
| Stomachaches | 1 (2%) | 3 (6%) | 0 | 4 (3%) | 0·22 |
| Dizziness | 0 | 0 | 0 | 0 | ·· |
| Headaches | 3 (6%) | 4 (8%) | 3 (6%) | 10 (7%) | 0·92 |
| Drowsiness | 1 (2%) | 4 (8%) | 3 (6%) | 8 (5%) | 0·36 |
| Motor Tics | 4 (8%) | 6 (12%) | 3 (6%) | 13 (9%) | 0·59 |
| Nightmares | 5 (10%) | 7 (14%) | 4 (8%) | 16 (11%) | 0·62 |
| Insomnia or restless sleeping | 17 (33%) | 11 (22%) | 9 (18%) | 37 (25%) | 0·19 |
| Decreased appetite | 13 (26%) | 10 (20%) | 3 (6%) | 26 (17%) | 0·032 o |
| Anxious | 18 (35%) | 16 (32%) | 16 (33%) | 50 (33%) | 0·93 |
| Bites finger nails | 11 (22%) | 14 (28%) | 9 (18%) | 34 (23%) | 0·51 |
| Irritable | 22 (43%) | 14 (28%) | 19 (39%) | 55 (37%) | 0·27 |
| Prone to crying | 16 (31%) | 17 (34%) | 10 (20%) | 43 (29%) | 0·29 |
| Depressed, sad, unhappy | 0 | 1 (2%) | 0 | 1 (0.7%) | 0·66 |
| Unusually happy | 5 (10%) | 6 (12%) | 3 (6%) | 14 (9%) | 0·65 |
| Uninterested in others | 5 (10%) | 1 (2%) | 2 (4%) | 8 (5%) | 0·25 |
| Talking little with others | 7 (14%) | 1 (2%) | 2 (4%) | 10 (7%) | 0·07 |
| Daydreams | 4 (8%) | 6 (12%) | 1 (2%) | 11 (7%) | 0·17 |
| Physical examination | |||||
| Weight changes from baseline to week 8 (Kg) j | −0·14 (1·05) | 0·46 (0·99) | 0·53 (0·64) | 0·29 (0·94) | 0·0012 p |
| BMI percentile at week 8 k | |||||
| <3 | 0 | 0 | 0 | 0 | ·· |
| 85-97 | 2 (5%) | 7 (18%) | 11 (26%) | 20 (16%) | 0·031 q |
| > 97 | 8 (19%) | 9 (23%) | 8 (19%) | 25 (20%) | 0·89 |
| Heart rate >120 bpm at 2 visits l | 1 (2%) | 0 | 3 (6%) | 4 (3%) | 0·12 |
| Blood pressure > 95th percentile 40 at 3 visits l | 2 (4%) | 2 (4%) | 0 | 4 (3%) | 0·55 |
| Exams m | |||||
| ECG at week 8, No. (%) | |||||
| Heart rate (bpm) >124 (F) or >123 (M) | 1 (2%) | 0 | 0 | 1 (1%) | >0·99 |
| PR interval (ms) <99 (F) or <98 (M) | 2 (4%) | 0 | 0 | 2 (1%) | 0·33 |
| PR interval (ms) >153 (F) or >152 (M) | 0 | 6 (13%) | 2 (4%) | 8 (6%) | 0·028 r |
| QRS duration (ms) >88 (F) or >92 (M) | 2 (4%) | 2 (4%) | 1 (2%) | 5 (4%) | 1·0 |
| QTc b interval (ms) >442 (F) or >448 (M) | 3 (8%) | 3 (9%) | 6 (18%) | 12 (12%) | 0·41 |
| Increased septal electrical forces | 0 | 0 | 1 (2%) | 1 (0.7%) | 0·66 |
| Short PR | 1 (2%) | 0 | 0 | 1 (0.7%) | 1·0 |
| Early transition | 3 (6%) | 0 | 1 (2%) | 4 (3%) | 0·32 |
| Early repolarization | 2 (4%) | 1 (2%) | 0 | 3 (2%) | 0·77 |
| Incomplete right bundle branch block (RBBB) | 0 | 1(2%) | 0 | 1 (0.7%) | 0·66 |
| End conduction delay | 1 (2%) | 3 (6%) | 1 (2%) | 5 (4%) | 0·53 |
| Laboratory Tests at week 8 | |||||
| ALT ≥41 U/L | 0 | 3 (6%) | 0 | 3 (2%) | 0·11 |
| AST ≥37 U/L | 7 (15%) | 4 (9%) | 5 (11%) | 16 (11%) | 0·61 |
| ALP ≥269 U/L | 10 (21%) | 13 (28%) | 7 (15%) | 30 (21%) | 0·32 |
| Bilirubin Total >1.0 mg/dL | 0 | 1 (2%) | 3.(6%) | 4 (3%) | 0·32 |
| Hemoglobin <11.7 g/dL | 5 (11%) | 1 (2%) | 1 (2%) | 7 (5%) | 0·22 |
| Leukocytes <5500/μL | 3 (7%) | 5 (11%) | 1 (2%) | 9 (6%) | 0·25 |
| Leukocytes >15500/μL | 2 (4%) | 0 | 2 (4%) | 4 (3%) | 0·47 |
| Platelet count >450 ×103/μL | 8 (17%) | 5 (11%) | 3 (6%) | 16 (11%) | 0·26 |
Data are mean (SD) or n (%). Abbreviations: ALP, alkaline phosphatase, ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; F, female; M, male; MPH+EI, methylphenidate + educational intervention; PLB+BPT, placebo + behavioral parenting training; PLB+EI, placebo + educational intervention; SERS, Barkley’s Side Effects Rating Scale SI conversion factor: To convert ALT, AST, and ALP from U/L to μkat/L, multiply by 0.0167. To convert Bilirubin Total from mg/dL to μmol/L, multiply by 17.104. To convert Hemoglobin from g/dL to g/L, multiply by 10. To convert Leucocytes from mil/μL to ×109/L, multiply by 0.001. To convert Leucocytes from ×103/μL to ×109/L, multiply by 1
For categorical variables, we used chi-square test of homogeneity, and multiple z-tests of two proportions with Bonferroni correction, for pairwise comparisons. Fisher’s Exact Test were used if more than 20% of cells have expected counts below 5. For continuous variables one-way ANOVA, and Scheffe post-hoc test was used.
Adverse events were classified as ‘mild’ if not required any further action.
Adverse events were classified as ‘moderate’ if required medical evaluation or interventions (e.g., dosage adjustment or the use of an over-the-counter medication).
Adverse events were classified as ‘severe’ if represented a serious medical threat (e.g., seizure).
Barkley’s Side Effects Rating Scale (SERS) total scores range from 0 to 103, with higher scores indicating more severe adverse events.
Number of children that presented score ≥7 at least once during treatment.
n=51 MPH+EI; n=49 PLB+BPT; n=48 PLB+EI
n=46 MPH+EI; n=47 PLB+BPT; n=45 PLB+EI
n=51 MPH+EI; n=50 PLB+BPT; n=49 PLB+EI
n=40 MPH+EI; n=38 PLB+BPT; n=43 PLB+EI
n=42 MPH+EI; n=40 PLB+BPT; n=43 PLB+EI
n=51 MPH+EI; n=50 PLB+BPT; n=48 PLB+EI
n=48 MPH+EI; n=47 PLB+BPT; n=47 PLB+EI
Pairwise comparisons: MPH+EI > PLB+BPT, PLB+EI
Pairwise comparisons: MPH+EI > PLB+EI
Pairwise comparisons: MPH+EI < PLB+BPT, PLB+EI
Pairwise comparisons: MPH+EI < PLB+EI
Pairwise comparisons: MPH+EI < PLB+EI
On the SERS scale, total score and decreased appetite score showed significant time by group interactions. Post-hoc pairwise comparisons for the SERS total score showed no group differences, and the MPH+EI group had more appetite reduction than PLB+BPT (mean difference= 1·99, CI95% 1·15, 2·82, p-value <0·0001, ES = 0·94, CI95% 0·54, 1·33) and PLB+EI (mean difference= 1·58, CI95% 0·73, 2·43, p-value <0·0001, ES = 0·75, CI 95% 0·35, 1·15) (appendix pp 34–35). There were time by group interactions for weight and BMI. Children in the MPH+EI group had weight and BMI reductions from baseline to endpoint but there were no endpoint differences between treatment groups (appendix pp 34–35). No abnormality requiring clinical interventions were detected in ECG and laboratory tests (Table 3). Four children (MPH+EI, n=1; PLB+EI, n=3) presented heart rate >120bpm at 2 visits, and 4 children (MPH+EI, n=2; PLB+BPT, n=2) presented high blood pressure at 3 visits (Table 3).
DISCUSSION
This trial assessed the efficacy and safety of MPH and BPT during 8 weeks of treatment in 153 preschool children aged 3-5 years old with ADHD. Results showed that MPH produced moderate reduction of frequency and severity of ADHD symptoms and associated improvement in global functioning in comparison to PLB+EI. BPT was not superior to PLB+EI in reducing ADHD symptoms, but produced improvement in global functioning. Most patients received their treatment as intended, adverse events were mild, and only 6% left the trial. The significance of this study stems from its rigorous methodology, including control for expectancy effects of medication and psychotherapy, assurance of parent blinding, detailed documentation of side-effects, and low drop-out rate. This allowed us to generate high-quality evidence to inform treatment recommendations for preschoolers with ADHD.
Effect size of MPH in reducing ADHD symptoms was −0·55, a moderate effect size consistent with findings from the PATS Study28 and lower than the −0·78 reported in school-age children29. There was no clear evidence of efficacy of BPT in reducing symptoms, although the direction of the effect on primary outcomes favored BPT consistently compared to PLB+EI. In sensitivity analysis, using parent report only, MPH and BPT were both superior to PLB+EI, with effect sizes of −0·73 and −0·53, respectively. Because our methods were designed to ensure parental blinding, report bias was likely minimal. Teachers did not detect significant effects of MPH or BPT vs. PLB+EI, which is contrary to the literature28. This may have occurred because treatment effects did not generalize to the school setting. Also, cultural aspects and characteristics of the educational system in Brazil (like higher tolerance to hyperactivity and resistance from teachers in relation to psychiatric diagnosis; preschools offer child-led play-based activities during half-day) may hinder identification of ADHD symptoms in this age group, as baseline scores informed by teachers were lower than those informed by parents. In addition, as the research team had less control over completion of SNAP-IV by teachers, more measurement error may have occurred, in contrast to clinician interviews with the parents.
Secondary outcomes indicated specific effects for each of the active treatments. Compared to both PLB+BPT and PLB+EI, MPH was associated with greater improvement in cognitive measures of attention. On the other hand, BPT was associated with improvement in irritability compared to MPH and PLB+EI. This is in line with theory and evidence showing that BPT is efficacious in the management of disruptive behaviors and functional problems during daily routines. It is relevant to note that slightly elevated although not statistically significant rates of comorbid oppositional defiant disorder and conduct disorder in PLB+BPT group vs. PLB+EI may have increased the chances of effect for the former. Reduction of irritability and/or noncompliance may have contributed to improvement in global functioning.
MPH produced more mild adverse events than the other two groups, and appetite reduction with MPH was identified consistently across different strategies of assessment. While children treated with MPH showed weight reduction over time, children on other groups presented weight gain, as expected. This effect and possible effects on height should be monitored over time and balanced against symptom improvement. There were two severe adverse effects, both not related to the study interventions. No ECG or laboratory abnormalities was associated with MPH use and, unlike previous studies10, there was no drop-out due to adverse events. Gradual and flexible titration and frequent clinical assessments may be related to higher safety and tolerability of medication treatment. Doses were optimized as planned, reaching absolute doses comparable to previous studies28 but with a twice daily regimen. This regimen may restrict the length of medication effect but may also minimize adverse effects in preschoolers, especially those related to appetite reduction at dinnertime and insomnia at the early bedtime that is typical in this age group.
Our study has limitations. First, the evidence is limited to 8 weeks, and different results could be seen with long-term treatment. The evidence generated here does not address questions such as the continued efficacy or cumulative adverse impact of either MPH or BPT over longer periods of time. Second, it was not possible to have complete teacher report for all participants and measurement error may have influenced their reports. Third, as in other randomized controlled trials conducted in university hospitals, results were obtained under optimal conditions and may not generalize to all settings because of staff characteristics (e.g., experience with preschoolers, intensive training and continuous supervision) or characteristics of the population included in the study. Our sample is very similar to the PATS Study28 sample in terms of age, sex distribution, severity of symptoms and functional impairment, presentation of symptoms and number of comorbid disorders. However, our sample had lower IQ scores and mothers were less educated. In our study, parents were highly motivated and attrition was low. Fourth, sample size calculation was based on reduction of ADHD symptoms, and analysis with different outcomes may be underpowered. Fifth, we did not include a fourth group combining methylphenidate and BPT. Finally, the study was conducted in a single center, which may limit generalization. Nevertheless, it was conducted in a hospital that serves a very diverse population of more than 20 million people. Moreover, a single-center study guarantees homogeneity in data collection and treatment.
Strengths of our study include a sham-BPT group which controlled for non-specific effects of psychotherapy and ensured blinding of parents, clinicians and independent evaluators; a relatively large sample size; outcomes informed by parents, teachers, clinicians, and objective measures; delivery of interventions as planned; and low attrition in all treatment groups. All primary and secondary outcomes were defined a priori and are reported here. Investigation of moderators and mediators of treatments effects will be reported in separate manuscripts.
MPH was well tolerated and effective in reducing the frequency and severity of ADHD symptoms and improving global functioning. BPT was not superior to PLB+EI in reducing the frequency and severity of ADHD symptoms but did improve global functioning. Participants showed adherence to both MPH and BPT. These results should be considered by clinicians making treatment recommendations, which will take into consideration symptom severity, presence of disruptive behaviors and/or irritability, functional impairment, parental dysfunction, family preference, accessibility of interventions, and other specific patient and family characteristics. Preschool children with ADHD should not be left untreated until they reach school age or impairment becomes severe, and should not receive treatments with no evidence base.
Supplementary Material
Research in context.
Evidence before this study
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that typically emerges in early childhood. There is insufficient evidence to support treatment recommendations for preschool children with ADHD. Behavioral parent training (BPT) produces improvements in measures of parenting but meta-analysis showed that the effect over reduction of ADHD symptoms is significant only with probably unblinded informants. Nevertheless, few studies have been conducted with blinded informants. Randomized controlled trials have demonstrated safety and efficacy of stimulants, with lower magnitude of effect sizes and more adverse events than reported for school-age children. Currently available network meta-analyses of medications have excluded preschoolers. No randomized controlled trial has tested the comparative efficacy and safety of methylphenidate and behavioral parent training ensuring blinding outcome assessment and with adequate control groups. Before the MAPPA Study, commencing in Aug 2016, we searched ClinicalTrials.gov, EMBASE and PubMed for randomized controlled trials assessing the efficacy of stimulant medications and BPT for participants younger than 6 years of age with ADHD. We additionally searched for reference lists of systematic reviews on the subject. No study was identified.
Added value of this study
We report the first rigorous randomized controlled trial designed to evaluate the efficacy and safety of stimulants and BPT as first line treatment for preschool ADHD. Our study has multiple strengths, including sham BPT to control for improvement due to non-specific aspects of psychotherapy and ensure blinding of parents and independent evaluators; a relatively large sample size; outcomes informed by parents, teachers, clinicians, and objective measures; detailed documentation of side-effects; low attrition. In this 8-week randomized controlled trial including 153 preschool children, methylphenidate reduced the frequency and severity of ADHD symptoms and improved global functioning. BPT improved global functioning. Methylphenidate produced more mild adverse events than other groups.
Implications of all the available evidence
MPH was well tolerated and effective in reducing the frequency and severity of ADHD symptoms and improving global functioning. BPT was not superior to PLB+EI in reducing the frequency and severity of ADHD symptoms but did improve global functioning. Participants showed adherence to both MPH and BPT. These results should be considered by clinicians making treatment recommendations, which will take into consideration symptom severity, presence of disruptive behaviors and/or irritability, functional impairment, parental dysfunction, family preference, accessibility of interventions, and other specific patient and family characteristics. Preschool children with ADHD should not be left untreated until they reach school age or impairment becomes severe, and should not receive treatments with no evidence base.
Acknowledgments:
Study staff: Adriana C. Argeu, Monike do N. Teixeira, Julia S. Torrezan, Leonardo R. S. Pinto. Clinical assessment and follow-up: Jordana V. de Oliveira MD, MSc, Livia L. R. Duncan MD, Maira Werneck MD. Evaluators: Caio B. Casella MD PhD candidate, Mauro V. M. Filho MD PhD candidate. Neuropsychological assesment: Aline M. Simionato, Ana Lucia G. Pereira, Cassiana G. Clemente, Cristiana P. Protasio, Cristiane S. Miranda, Fabiana C. Noronha, Luciana B. Garbin, Thais A. Vizoná. Behavioral parent training: Nicholas Long, PhD. Behavioral parent training therapists: Adriana S. U. Rossi PhD, Rodolfo R. Dib. Educational Intervention protocol: Cristiane Abe da Costa. Educational Intervention supervision: Cristiane Abe da Costa. Educational Intervention therapists: Maiza de Fátima S. Santos, Regiane R. Marinho. Interviewers: Alex Pedro da Silva, Anoilton do Rosário L. Junior, Ayrton S. A. Ferreira, Camila D. De Marco, Christie V. M. de A. Gondim, Gabriella R. Pontes, Giovanna M. Marcelino, Jamila Aparecida R. Pimentel, Julia M. Nicolella, Juliana S. Mourão, Larissa A. Amaral, Larissa V. B. de Araujo, Leticia L. A. Cruz, Ligia da C. Lucena, Livia A. Fernandes, Luan R. Serejo, Marcelly Quaglia, Maria Lucimar de O. Pereira, Marina K. G. de Azevedo, Marina Marchetti, Monicke de O. Lima, Morgana D. Ledesma, Natana L. R. Paulino, Neide Aparecida Piva, Patricia S. Campos, Ricardo F. da Silva, Sophia Maria Boff, Thalita S. Chieregato, Valeria A. do C de Araujo, Vanessa R. Ramos, Vitor P. M. Guida.
Source of Funding:
This study was supported by Brazilian National Council for Scientific and Technological Development, CNPq (grant 466859/2014-7 and 462470/2014-8) and São Paulo Research Foundation, FAPESP (grant 2016/22455-8).
Declaration of Interests:
Dr. Polanczyk, in the last 3 years, has been a consultant, member of advisory board, and/or speaker for Takeda, Medice, Aché, Novo Nordisk, Pfizer, and Abbott; he has received royalties from Editora Manole. Dr. Rohde has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Aché, Bial, Medice, Novartis/Sandoz, Pfizer/Upjohn, and Shire/Takeda in the last three years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by Dr. Rohde have received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Novartis/Sandoz and Shire/Takeda. Dr. Rohde has received authorship royalties from Oxford Press and ArtMed. The other authors have no conflicts of interest to disclose.
Footnotes
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Data sharing
Anonymized participant data will be made available when the trial is published, upon requests directed to the corresponding author. Proposals will be reviewed and approved by the investigators on the basis of scientific merit. After approval of a proposal, data can be shared through a secure online platform after signing a data access agreement. All data will be made available for a minimum of 5 years from the publication.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Anonymized participant data will be made available when the trial is published, upon requests directed to the corresponding author. Proposals will be reviewed and approved by the investigators on the basis of scientific merit. After approval of a proposal, data can be shared through a secure online platform after signing a data access agreement. All data will be made available for a minimum of 5 years from the publication.