Two single arm trials of AKL-T01, a digital therapeutic for adolescents and adults with ADHD.

Inattention symptoms represent a key driver of functional impairment in ADHD and often persist into adolescence and adulthood, underscoring a need for novel treatments targeting attentional control. We evaluated AKL-T01-a digital therapeutic that is FDA-cleared for children 8-12 y with ADHD-in adolescents and adults with ADHD in two independent single-arm trials: STARS-ADHD-Adolescent, a 4-week trial in adolescents 13-17 y (n = 162 enrolled), and STARS-ADHD-Adult, a 6-week trial in adults 18 and older (n = 221 enrolled). AKL-T01 was linked with improvements on the Test of Variables of Attention (TOVA®) Attention Comparison Score (ACS) of 2.6 (95% CI: 2.02, 3.26; p < 0.0001) in adolescents and 6.5 in adults (95% CI: 5.35, 7.57; p < 0.0001), along with improvements in secondary endpoints. 15 participants reported adverse device effects, all mild or moderate. Though limited by a single-arm design, results provide preliminary support for the safety and efficacy of AKL-T01 for adolescents and adults with ADHD.

Evaluation of an artificial intelligence-based medical device for diagnosis of autism spectrum disorder.

Autism spectrum disorder (ASD) can be reliably diagnosed at 18 months, yet significant diagnostic delays persist in the United States. This double-blinded, multi-site, prospective, active comparator cohort study tested the accuracy of an artificial intelligence-based Software as a Medical Device designed to aid primary care healthcare providers (HCPs) in diagnosing ASD. The Device combines behavioral features from three distinct inputs (a caregiver questionnaire, analysis of two short home videos, and an HCP questionnaire) in a gradient boosted decision tree machine learning algorithm to produce either an ASD positive, ASD negative, or indeterminate output. This study compared Device outputs to diagnostic agreement by two or more independent specialists in a cohort of 18-72-month-olds with developmental delay concerns (425 study completers, 36% female, 29% ASD prevalence). Device output PPV for all study completers was 80.8% (95% confidence intervals (CI), 70.3%-88.8%) and NPV was 98.3% (90.6%-100%). For the 31.8% of participants who received a determinate output (ASD positive or negative) Device sensitivity was 98.4% (91.6%-100%) and specificity was 78.9% (67.6%-87.7%). The Device's indeterminate output acts as a risk control measure when inputs are insufficiently granular to make a determinate recommendation with confidence. If this risk control measure were removed, the sensitivity for all study completers would fall to 51.6% (63/122) (95% CI 42.4%, 60.8%), and specificity would fall to 18.5% (56/303) (95% CI 14.3%, 23.3%). Among participants for whom the Device abstained from providing a result, specialists identified that 91% had one or more complex neurodevelopmental disorders. No significant differences in Device performance were found across participants' sex, race/ethnicity, income, or education level. For nearly a third of this primary care sample, the Device enabled timely diagnostic evaluation with a high degree of accuracy. The Device shows promise to significantly increase the number of children able to be diagnosed with ASD in a primary care setting, potentially facilitating earlier intervention and more efficient use of specialist resources.

The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome.

OBJECTIVE: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). METHODS: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit-containing extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd), gaboxadol 10 mg morning dose and 15 mg evening dose (bid), or placebo morning and evening dose. Safety and tolerability were monitored throughout the study. Prespecified exploratory efficacy end points included adapted Clinical Global Impression-Severity and Clinical Global Impression-Improvement (CGI-I) scales, which documented the clinical severity at baseline and change after treatment, respectively. RESULTS: Eighty-eight individuals were randomized. Of 87 individuals (aged 13-45 years) who received at least 1 dose of study drug, 78 (90%) completed the study. Most adverse events (AEs) were mild to moderate, and no life-threatening AEs were reported. Efficacy of gaboxadol, as measured by CGI-I improvement in an exploratory analysis, was observed in gaboxadol qd vs placebo (p = 0.0006). CONCLUSION: After 12 weeks of treatment, gaboxadol was found to be generally well-tolerated with a favorable safety profile. The efficacy as measured by the AS-adapted CGI-I scale warrants further studies. CLINICALTRIALSGOV IDENTIFIER: NCT02996305. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for individuals with AS, gaboxadol is generally safe and well-tolerated.

Pediatric Prolonged-Release Melatonin for Sleep in Children with Autism Spectrum Disorder: Impact on Child Behavior and Caregiver's Quality of Life.

A randomized, 13-weeks, placebo-controlled double-blind study in 125 subjects aged 2-17.5 years with Autism Spectrum Disorder or Smith-Magenis syndrome and insomnia demonstrated efficacy and safety of easily-swallowed prolonged-release melatonin mini-tablets (PedPRM; 2-5 mg) in improving sleep duration and onset. Treatment effects on child behavior and caregiver's quality of life were evaluated. PedPRM treatment resulted in significant improvement in externalizing but not internalizing behavior (Strengths and Difficulties questionnaire; SDQ) compared to placebo (p = 0.021) with clinically-relevant improvements in 53.7% of PedPRM-treated versus 27.6% of placebo-treated subjects (p = 0.008). Caregivers' quality of life also improved with PedPRM versus placebo (p = 0.010) and correlated with the change in total SDQ (p = 0.0005). PedPRM alleviates insomnia-related difficulties, particularly externalizing behavior in the children, subsequently improving caregivers' quality of life.

Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies.

Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension.

OBJECTIVE: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. METHODS: A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. RESULTS: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. CONCLUSIONS: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study.

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder-Not Otherwise Specified, and a score ≥17 on the Aberrant Behavior Checklist (ABC)-Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted.

Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder.

OBJECTIVE: Converging lines of evidence point to the existence of immune dysfunction in autism spectrum disorder (ASD), which could directly affect several key neurodevelopmental processes. Previous studies have shown higher cytokine levels in patients with autism compared with matched controls or subjects with other developmental disorders. In the current study, we used plasma-cytokine profiling for 25 discordant sibling pairs to evaluate whether these alterations occur within families with ASD. METHODS: Plasma-cytokine profiling was conducted using an array-based multiplex sandwich ELISA for simultaneous quantitative measurement of 40 unique targets. We also analyzed the correlations between cytokine levels and clinically relevant quantitative traits (Vineland Adaptive Behavior Scale in Autism (VABS) composite score, Social Responsiveness Scale (SRS) total T score, head circumference, and full intelligence quotient (IQ)). In addition, because of the high phenotypic heterogeneity of ASD, we defined four subgroups of subjects (those who were non-verbal, those with gastrointestinal issues, those with regressive autism, and those with a history of allergies), which encompass common and/or recurrent endophenotypes in ASD, and tested the cytokine levels in each group. RESULTS: None of the measured parameters showed significant differences between children with ASD and their related typically developing siblings. However, specific target levels did correlate with quantitative clinical traits, and these were significantly different when the ASD subgroups were analyzed. It is notable that these differences seem to be attributable to a predisposing immunogenetic background, as no other significant differences were noticed between discordant sibling pairs. Interleukin-1ß appears to be the cytokine most involved in quantitative traits and clinical subgroups of ASD. CONCLUSIONS: In the present study, we found a lack of significant differences in plasma-cytokine levels between children with ASD and in their related non-autistic siblings. Thus, our results support the evidence that the immune profiles of children with autism do not differ from their typically developing siblings. However, the significant association of cytokine levels with the quantitative traits and the clinical subgroups analyzed suggests that altered immune responses may affect core feature of ASD.

Autism and increased paternal age related changes in global levels of gene expression regulation.

A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.

Atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder.

INTRODUCTION: This study compared two atomoxetine titration dosing schedules and two atomoxetine maintenance doses for treating adolescent attention-deficit/hyperactivity disorder (ADHD) inattention and hyperactivity/impulsivity. METHODS: Adolescents (N = 267) were randomized to a slow or fast titration schedule. Patients who responded continued on a 40-week maintenance treatment, randomized to either 0.8 or 1.4 mg/kg/day. RESULTS: During the acute period, significant benefit was demonstrated with both titration schedules on the ADHD Rating Scale total score. Although patients in both groups maintained benefit relative to week 0, statistically significant loss of benefit was found for patients maintained on 0.8 mg/kg/day but not on 1.4 mg/kg/day. A similar pattern was observed on the Clinical Global Impressions-ADHD-Severity scores and Life Participation Scale for ADHD-Child Version scores. Mean grades for most subjects improved for patients in both maintenance treatment groups although most improvements were not statistically significant. CONCLUSIONS: In adolescents with ADHD, treatment benefit at 8 weeks was better maintained long-term with 1.4 mg/kg/day than with 0.8 mg/kg/day. Improvement in adaptive functioning and age-appropriate developmental function was also demonstrated. Atomoxetine 0.8 and 1.4 mg/kg/day were equally well tolerated. CLINICAL TRIALS REGISTRY: Maintenance of benefit with atomoxetine hydrochloride in adolescents with ADHD, NCT00191035.

A double-blind, placebo-controlled trial of oral human immunoglobulin for gastrointestinal dysfunction in children with autistic disorder.

Controversy exists regarding the extent and possible causal relationship between gastrointestinal symptoms and autism. A randomized, double-blind, placebo-controlled, parallel groups, dose-ranging study of oral, human immunoglobulin (IGOH 140, 420, or 840 mg/day) was utilized with 125 children (ages 2-17 years) with autism and persistent GI symptoms. Endpoint analysis revealed no significant differences across treatment groups on a modified global improvement scale (validated in irritable bowel syndrome studies), number of daily bowel movements, days of constipation, or severity of problem behaviors. IGOH was well-tolerated; there were no serious adverse events. This study demonstrates the importance of conducting rigorous trials in children with autism and casts doubt on one GI mechanism presumed to exert etiological and/or symptomatic effects in this population.

A randomized, double-blind, placebo-controlled, parallel-group study of methylphenidate transdermal system in pediatric patients with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and safety of methylphenidate transdermal system compared with placebo, using osmotic-release oral system (OROS) methylphenidate as a reference therapy. METHOD: We conducted a 7-week, randomized, double-blind, double-dummy, placebo-controlled trial in children diagnosed with attention-deficit/hyperactivity disorder by DSM-IV-TR criteria, within a community setting. The study was conducted from August 2004 to February 2005. Participants were randomly assigned to 1 of 3 treatments: methylphenidate transdermal system patch plus placebo capsule (N = 100), OROS methylphenidate capsule plus placebo patch (N = 94), or placebo capsule plus placebo patch (N = 88). Over 5 weeks, once-daily doses were optimized using 10-, 15-, 20-, and 30-mg methylphenidate transdermal system patches (9-hour wear time) or 18-, 27-, 36-, and 54-mg OROS methylphenidate capsules. Thereafter, optimal treatment doses were maintained for 2 weeks with blinded ratings of attention, behavior, and academic performance occurring at the end of each week. The primary efficacy measure was the clinician-rated ADHD Rating Scale-Version IV (ADHD-RS-IV). Additional measures included teacher, parent, and other clinician rating scales. Safety and tolerability were assessed throughout the study. RESULTS: The mean change from baseline in ADHD-RS-IV scores was greater for participants receiving methylphenidate transdermal system and OROS methylphenidate treatments compared with placebo (p < .0001). Similar results were observed for parent and teacher rating scales. More participants receiving active treatments compared with placebo were rated as improved by clinicians and parents (p < .0001). Adverse events were generally mild or moderate in intensity, and the most common included decreased appetite, nausea, vomiting, and insomnia. CONCLUSIONS: The results of this study suggest that the methylphenidate transdermal system is an efficacious treatment option for children with attention-deficit/hyperactivity disorder. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00444574.

A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: With this study we assessed the efficacy and safety of an extended-release formulation of guanfacine compared with placebo for the treatment of children and adolescents with attention-deficit/hyperactivity disorder. METHODS: In this multicenter, double-blind, placebo-controlled, fixed-dosage escalation study, patients aged 6 to 17 years were randomly assigned to 1 of 3 treatment groups of guanfacine extended release (2, 3, or 4 mg/day) or placebo for 8 weeks. The primary outcome measurement was the Attention-Deficit/Hyperactivity Disorder Rating Scale IV total score. Secondary measurements included Clinical Global Impression of Improvement, Parent's Global Assessment, Conners' Parent Rating Scale-Revised: Short Form, and Conners' Teacher Rating Scale-Revised: Short Form. RESULTS: A total of 345 patients were randomly assigned to placebo (n = 86) or guanfacine extended release 2 mg (n = 87), 3 mg (n = 86), or 4 mg (n = 86) treatment groups. Least-squares mean changes from baseline to the end point in Attention-Deficit/Hyperactivity Disorder Rating Scale IV total scores were significant in all groups of children taking guanfacine extended release: -16.18 in the 2-mg group, -16.43 in the 3-mg group, and -18.87 in the 4-mg group, compared with -8.48 in the placebo group. All groups of children taking guanfacine extended release showed significant improvement on hyperactivity/impulsivity and inattentiveness subscales of the Attention-Deficit/Hyperactivity Disorder Rating Scale IV, Clinical Global Impression of Improvement, Parent's Global Assessment, Conners' Parent Rating Scale-Revised: Short Form, and Conners' Teacher Rating Scale-Revised: Short Form assessments compared with placebo. The most commonly reported treatment-emergent adverse events were headache, somnolence, fatigue, upper abdominal pain, and sedation. Small to modest changes in blood pressure, pulse rate, and electrocardiogram parameters were observed but were not clinically meaningful. CONCLUSIONS: Guanfacine extended release met the primary and secondary efficacy end points. It was well tolerated and effective compared with placebo.

Long-term, open-label extension study of guanfacine extended release in children and adolescents with ADHD.

INTRODUCTION: Guanfacine is a noradrenergic agonist that is believed to improve symptoms of attention-deficit/hyperactivity disorder (ADHD) through selective actions at alpha2A-adrenoceptors in the prefrontal cortex. A recent double-blind, multicenter trial supports the efficacy and safety of guanfacine extended release (GXR) for pediatric ADHD. This long-term, open-label extension was conducted to study the safety profile and effectiveness of GXR for up to 2 years. METHODS: Subjects were 240 children 6-17 years of age with a diagnosis of ADHD who participated in the preceding randomized trial. GXR was initiated at 2 mg/day and titrated as needed in 1-mg increments to a maximum of 4 mg/day to achieve optimal clinical response. RESULTS: The most common adverse events were somnolence (30.4%), headache (26.3%), fatigue (14.2%), and sedation (13.3%). Somnolence, sedation, and fatigue were usually transient. Cardiovascular-related adverse events were uncommon, although small reductions in mean blood pressure and pulse rate were evident at monthly visits. ADHD Rating Scale, Version IV, total and subscale scores improved significantly from baseline to endpoint for all dose groups (P<.001 for all comparisons, intent-to-treat population). CONCLUSION: Long-term treatment with GXR was generally safe for up to 24 months of treatment, and effectiveness was maintained over this treatment period.

Oral human immunoglobulin for children with autism and gastrointestinal dysfunction: a prospective, open-label study.

Immunoglobulin secretion onto mucosal surfaces is a major component of the mucosal immune system. We hypothesized that chronic gastrointestinal (GI) disturbances associated with autistic disorder (AD) may be due to an underlying deficiency in mucosal immunity, and that orally administered immunoglobulin would be effective in alleviating chronic GI dysfunction in these individuals. In this pilot study, twelve male subjects diagnosed with AD were evaluated using a GI severity index (GSI) while receiving daily dosing with encapsulated human immunoglobulin. Following eight weeks of treatment, 50% of the subjects met prespecified criteria for response in GI signs and symptoms and showed significant behavioral improvement as assessed by the Autism Behavior Checklist and parent and physician rated Clinical Global Impression of Improvement.