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ObjectiveTo determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available.MethodsThis was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT.ResultsAll dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns–Visual Analog Scale, and Clinical Global Impression Scale–Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure.ConclusionThese results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials.Classification of evidenceThis study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.

Rett syndrome (RTT) is a debilitating neurodevelopmental disorder with no approved treatments. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor 1. In a phase 2, placebo-controlled trial in 82 females with RTT aged 5-15 years, a significant (p ≤ 0.042) improvement over placebo was observed with the highest trofinetide dose (200 mg/kg twice daily [BID]) on three measures: Rett Syndrome Behaviour Questionnaire (RSBQ), Clinical Global Impression-Improvement (CGI-I), and RTT-Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC-VAS). Trofinetide was well tolerated at all doses (50, 100, and 200 mg/kg BID). A phase 3 trial utilizing disease-specific and novel scales was designed to investigate the efficacy and safety of trofinetide in girls and women with RTT.This 12-week, double-blind, randomized, placebo-controlled study (LAVENDER; NCT04181723) will evaluate trofinetide in 187 females, aged 5-20 years, with RTT. Co-primary endpoints are the RSBQ and CGI-I scales. Clinical domains of the CGI-I include communication, ambulation, hand use, seizures, attentiveness, and social (eye contact) and autonomic (breathing) aspects. Secondary endpoints will leverage four novel RTT-specific clinician ratings (derived from the RTT-DSC-VAS) of hand function, ambulation, ability to communicate, and verbal communication, and existing scales, to evaluate other core symptoms of RTT, quality of life and caregiver burden. A 40-week, open-label extension study will follow.This study was designed using disease-specific scales optimized to demonstrate changes in core symptoms of RTT and may provide the first phase 3 data demonstrating drug efficacy in individuals with RTT.Clinicaltrials.govNCT04181723.

We analyze the safety and tolerability of trofinetide and provide a preliminary evaluation of its efficacy in adolescent and adult males with fragile X syndrome.This study was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, parallel group study of the safety and tolerability of orally administered trofinetide in 72 adolescent and adult males with fragile X syndrome. Subjects were randomly assigned in a 1:1:1 ratio to 35 or 70 mg/kg twice daily trofinetide or placebo for 28 days. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and concomitant medications. Efficacy measurements were categorized into four efficacy domains, which related to clinically relevant phenotypic dimensions of impairment associated with fragile X syndrome.Both 35 and 70 mg/kg dose levels of trofinetide were well tolerated and appeared to be generally safe. Trofinetide at the 70 mg/kg dose level demonstrated efficacy compared with placebo based on prespecified criteria. On the basis of a permutation test, the probability of a false-positive outcome for the achieved prespecified success was 0.045. In the group analysis, improvement from treatment baseline was demonstrated on three fragile X syndrome-specific outcome measures.Trofinetide was well tolerated in adolescent and adult males with fragile X syndrome. Despite the relatively short duration of the study, a consistent signal of efficacy at the higher dose was observed in both caregiver and clinician assessments, based on a novel analytical model incorporating evaluation of multiple key symptom areas of fragile X syndrome. This finding suggests a potential for trofinetide treatment to provide clinically meaningful improvement in core fragile X syndrome symptoms.

Rett syndrome (RTT) requires total caregiver attention and leads to potential difficulties throughout life. The Caregiver Burden Inventory, designed for Alzheimer disease, was modified to a RTT Caregiver Inventory Assessment (RTT CIA). Reliability and face, construct, and concurrent validity were assessed in caregivers of individuals with RTT. Chi-square or Fisher’s exact test for categorical variables and t-tests or Wilcoxon two-sample tests for continuous variables were utilized. Survey completed by 198 caregivers; 70 caregivers completed follow-up assessment. Exploratory factor analysis revealed good agreement for Physical Burden, Emotional Burden, and Social Burden. Internal reliability was high (Cronbach’s alpha: 0.898). RTT CIA represents a reliable and valid measure, providing a needed metric of caregiver burden in this disorder.

Rett syndrome is a genetically based neurodevelopmental disorder. Although the clinical consequences of Rett syndrome are profound and lifelong, currently no approved drug treatments are available specifically targeted to Rett symptoms. High quality outcome measures, specific to the core symptoms of a disorder are a critical component of well-designed clinical trials for individuals with neurodevelopmental disorders. The Clinical Global Impression Scale is a measure of global clinical change with strong face validity that has been widely used as an outcome measure in clinical trials of central nervous system disorders. Despite its favorable assay sensitivity in clinical trials, as a global measure, the Clinical Global Impression Scale is not specific to the signs and symptoms of the disorder under study. Development of key anchors for the scale, specific to the disorder being assessed, holds promise for enhancing the validity and reliability of the measure for disorders such as Rett syndrome.

This study aimed to determine the safety and tolerability of trofinetide and to evaluate efficacy measures in adolescent and adult females with Rett syndrome, a serious and debilitating neurodevelopmental condition for which no therapies are available for its core features.This was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, dose-escalation study of the safety and tolerability of trofinetide in 56 adolescent and adult females with Rett syndrome. Subjects were randomly assigned in a 2:1 ratio to 35 mg/kg twice daily of trofinetide or placebo for 14 days; 35 mg/kg twice daily or placebo for 28 days; or 70 mg/kg twice daily or placebo for 28 days. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and concomitant medications. Efficacy measurements were categorized into four efficacy domains, which related to clinically relevant, phenotypic dimensions of impairment associated with Rett syndrome.Both 35 mg/kg and 70 mg/kg dose levels of trofinetide were well tolerated and generally safe. Trofinetide at 70 mg/kg demonstrated efficacy compared with placebo based on prespecified criteria.Trofinetide was well tolerated in adolescent and adult females with Rett syndrome. Although this study had a relatively short duration in a small number of subjects with an advanced stage of disease, consistent efficacy trends at the higher dose were observed in several outcome measures that assess important dimensions of Rett syndrome. These results represented clinically meaningful improvement from the perspective of the clinicians as well as the caregivers.

Social communication impairments are a core deficit in autism spectrum disorder. Social communication deficit is also an early indicator of autism spectrum disorder and a factor in long-term outcomes. Thus, this symptom domain represents a critical treatment target. Identifying reliable and valid outcome measures for social communication across a range of treatment approaches is essential. Autism Speaks engaged a panel of experts to evaluate the readiness of available measures of social communication for use as outcome measures in clinical trials. The panel held monthly conference calls and two face-to-face meetings over 14 months. Key criteria used to evaluate measures included the relevance to the clinical target, coverage of the symptom domain, and psychometric properties (validity and reliability, as well as evidence of sensitivity to change). In all, 38 measures were evaluated and 6 measures were considered appropriate for use, with some limitations. This report discusses the relative strengths and weaknesses of existing social communication measures for use in clinical trials and identifies specific areas in need of further development.

* Abbreviations: AIR-P — : Autism Intervention Research Network on Physical Health ASD — : autism spectrum disorder ATN — : Autism Treatment Network CER — : comparative effectiveness research CTSAs — : Clinical Translational Science programs Autism spectrum disorders (ASDs) represent complex neurodevelopmental disorders with multiple etiologies.1 The resulting variability of behavioral, medical, and developmental concerns that affect individuals with ASDs has made it extremely difficult to predict which treatments work best for which individuals. Developing effective treatments and improving care for individuals with ASDs throughout the life span remain urgent priorities. Comprehensive coordinated care for individuals with ASDs will require further advances in our knowledge of medical and behavioral interventions and a health care system that can deliver them consistently. Over the past 7 years, the Autism Speaks Autism Treatment Network (ATN) and more recently the Autism Intervention Research Network on Physical Health (AIR-P) have significantly increased understanding of the prevalence, nature, and treatment of medical conditions in children with ASDs, such as gastrointestinal conditions, sleep disorders, metabolic disorders, and seizures. The network has pioneered in standardizing the clinical evaluation of children with ASDs, based on a comprehensive, multidisciplinary model of care. The network has also developed key partnerships that have helped the field move from limited consensus toward evidence-based autism-specific guidelines in key areas of medical concern, and has acquired the infrastructure and expertise to develop more targeted treatment studies that can help move the most effective therapies through the research pipeline and into the hands of consumers. The ATN has led in the application of quality improvement methods to autism care and in systematic efforts to bring the experience and lessons of the network to broader communities of professionals and parents. This effort, led by Autism Speaks, has allowed strong synergy among research, clinical, and family communities. Key areas of continued growth for the research activities of network include (1) on-going enhancement of research infrastructure, including increased availability of biological samples; (2) expansion of the research agenda to include more focused research … Address correspondence to James M. Perrin, MD, Department of Pediatrics, Harvard Medical School, MassGeneral Hospital for Children, 100 Cambridge St, #1542, Boston, MA 02114. E-mail: jperrin{at}partners.org

* Abbreviations: ASD — : autism spectrum disorder GI — : gastrointestinal 5-HT — : serotonin Autism spectrum disorders (ASDs) are a set of complex neurodevelopmental disorders defined behaviorally by impaired social interaction, delayed and disordered language, repetitive or stereotypic behavior, and a restricted range of interests. ASDs represent a significant public health issue with recent estimates indicating that as many as 1% of children in the United States are diagnosed with an ASD.1,2 Many individuals with ASDs have symptoms of associated medical conditions, including seizures, sleep problems, metabolic conditions, and gastrointestinal (GI) disorders, which have significant health, developmental, social, and educational impacts. Gastrointestinal complaints are a commonly reported concern for parents and may be related to problem behaviors and other medical issues such as dysregulated sleep (ATN Annual Registry Report, unpublished data, November 2009).3 Despite the magnitude of these issues, potential GI problems are not routinely considered in ASD evaluations. This likely reflects several factors, including variability in reported rates of GI disorders, controversies regarding the relationship between GI symptoms and the putative causes of autism, the limited verbal capacity of many ASD patients, and the lack of recognition by clinicians that certain behavioral manifestations in children with ASDs are indicators of GI problems (eg, pain, discomfort, or nausea).4–10 Whether GI issues in this population are directly related to the pathophysiology of autism, or are strictly a comorbid condition of ASD remains to be determined, but clinical practice and research to date indicate the important role of GI conditions in ASDs and their impact on children as well as their parents and clinicians.9 On November 15, 2009, a symposium addressing these issues was organized as an adjunct to the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. A … Address correspondence to Daniel L. Coury, MD, Professor of Pediatrics and Psychiatry, The Ohio State University, Chief, Developmental & Behavioral Pediatrics, Nationwide Children's Hospital, 700 Children's Dr, Timken G-350, Columbus OH 43205-2696

This study examined how children and adolescents with Williams syndrome (WS; ages 8 years, 0 months [8;0]–14;5) used referential devices (determiners and pronouns), tense, and connectives to create cohesion in oral narratives based on a storybook compared to typically developing mentally and chronologically age-matched children. WS children used cohesive devices in narratives similarly to mentally matched children, but their performance differed from the chronologically matched children only for referential cohesion. WS children's grammatical error rates were similar to both the mentally and chronologically matched children. Implications for the characterization of the language profile of individuals with WS and considerations for the focus of future narrative research are discussed.

Restricted interests and repetitive behaviors vary widely in type, frequency, and intensity among children and adolescents with autism spectrum disorder. They can be stigmatizing and interfere with more constructive activities. Accordingly, restricted interests and repetitive behaviors may be a target of intervention. Several standardized instruments have been developed to assess restricted interests and repetitive behaviors in the autism spectrum disorder population, but the rigor of psychometric assessment is variable. This article evaluated the readiness of available measures for use as outcome measures in clinical trials. The Autism Speaks Foundation assembled a panel of experts to examine available instruments used to measure restricted interests and repetitive behaviors in youth with autism spectrum disorder. The panel held monthly conference calls and two face-to-face meetings over 14 months to develop and apply evaluative criteria for available instruments. Twenty-four instruments were evaluated and five were considered “appropriate with conditions” for use as outcome measures in clinical trials. Ideally, primary outcome measures should be relevant to the clinical target, be reliable and valid, and cover the symptom domain without being burdensome to subjects. The goal of the report was to promote consensus across funding agencies, pharmaceutical companies, and clinical investigators about advantages and disadvantages of existing outcome measures.

Despite the high rate of anxiety in individuals with autism spectrum disorder (ASD), measuring anxiety in ASD is fraught with uncertainty. This is due, in part, to incomplete consensus on the manifestations of anxiety in this population. Autism Speaks assembled a panel of experts to conduct a systematic review of available measures for anxiety in youth with ASD. To complete the review, the panel held monthly conference calls and two face-to-face meetings over a fourteen-month period. Thirty eight published studies were reviewed and ten assessment measures were examined: four were deemed appropriate for use in clinical trials, although with conditions; three were judged to be potentially appropriate, while three were considered not useful for clinical trials assessing anxiety. Despite recent advances, additional relevant, reliable and valid outcome measures are needed to evaluate treatments for anxiety in ASD.

* Abbreviations: AIR-P — : Autism Intervention Research Network on Physical Health ASD — : autism spectrum disorder ATN — : Autism Treatment Network FAC — : Family Advisory Committee GI — : gastrointestinal HRSA — : Health Resources and Services Administration NICHQ — : National Initiative for Children’s Healthcare Quality Autism spectrum disorders (ASDs) are a group of highly prevalent, lifelong neurodevelopmental disorders affecting social, communicative, and behavioral functioning. Recent studies estimate the prevalence of ASDs as 1 in 88,1,2 indicating the public health importance of the disorders and making the development of effective care and treatment of ASD an urgent priority. Among the health care concerns for children and youth with ASD is a major need to strengthen awareness and treatment of associated medical conditions with standardized, comprehensive approaches to evaluation, treatment, and monitoring. Many individuals with ASD have symptoms associated with underlying medical conditions, including seizures, sleep problems, gastrointestinal (GI) disorders, psychiatric conditions, nutritional deficiencies, and metabolic conditions; when left untreated, these conditions may not only compromise general health but also have clear effects on behavior, development, and educational outcomes for individuals with ASD. The problems that many children with ASD have with communication make the diagnosis and monitoring of medical conditions more challenging. Furthermore, the underlying biology of ASD may change the manifestations of various medical conditions and their response to treatment. Thus, special attention to these conditions is crucial for improving the quality of life for individuals with ASD. Children and adolescents with ASD encounter difficulties obtaining appropriate and necessary health care services. They have decreased access to medical specialists,3–5 coupled with increased medical expenditures and unmet needs, compared with other children with special health care needs and typically developing children.6,7 Autism Speaks and its predecessor, Cure Autism Now, have recognized the significant unmet medical needs among children and adolescents with ASD as well as the many gaps in knowledge among providers regarding the general health care challenges of individuals with ASD. Parents shared their frustrations and all too familiar tales of having to travel far distances … Address correspondence to James M. Perrin, MD, Department of Pediatrics, Harvard Medical School, MassGeneral Hospital for Children, 100 Cambridge St #1542, Boston, MA 02114. E-mail: jperrin{at}partners.org

Autism spectrum disorders (ASDs) are a group of a neurodevelopmental disorders affecting social, communicative, and behavioral functioning. ASD is a heterogeneous group of disorders, often accompanied by associated medical issues. Thus, the development of effective treatments is a complex task requiring consideration of diverse etiologic and phenotypic characteristics. Recent attention to the diagnosis and treatment of medical conditions in ASD children has led to the formation of a new international collaboration to improve autism care, the Autism Treatment Network (ATN).Numerous studies have highlighted the high prevalence of gastrointestinal and sleep disorders among ASD children. Problems in communication - including being nonverbal - make the diagnosis and treatment of these conditions more difficult. Although a number of studies suggest links between neurologic impairments and gastrointestinal dysfunction and disordered sleep, these relationships remain unproven. Recent work by the ATN has begun the development of clinical guidelines in these areas, based on clinical consensus, adapting the model developed by the Cystic Fibrosis Foundation. New funding has also supported the network's development of a robust clinical research program focused on improving the physical health and care of children with ASD. These efforts promise more systematic and consistent approaches to diagnosis and treatment of these conditions.Improved understanding of the underlying pathology of ASD and associated conditions, and the development of a common purpose across multiple treating sites, can improve the consistent and coordinated healthcare of children with autism.