The Content of Usual Clinical Care for Youth with Primary Anxiety Problems.

The current study was designed to describe usual clinical care for youth with primary anxiety problems in community mental health centers. The observer-rated Therapy Process Observational Coding System for Child Psychotherapy - Revised Strategies scale (TPOCS-RS), designed to assess therapeutic techniques from five theory-based domains, was used to code sessions (N = 403) from the usual clinical care group of two randomized effectiveness trials: (a) Youth Anxiety Study (YAS) with 21 youth (M age = 10.44 years, SD = 1.91; 49.2% Latinx; 46.6%, 53.4% male) and 16 clinicians (77.5% female; 43.8% White), and (b) Child STEPS Multisite Trial with 17 youth (M age = 10.00 years, SD = 1.87; 58.8% male; 41.2% White) and 13 clinicians (M age = 40.00 years; SD = 9.18; 76.9% female; 61.5% White). The average number of TPOCS-RS items observed per treatment session was more than 10, and multiple techniques were used together in each session. All TPOCS-RS items were observed at least once throughout a clinical case, and most items reoccurred (i.e., observed in two or more sessions). The dosage of TPOCS-RS in all items was below 5 on a 7-point scale. In conclusion, clinicians in both usual care samples used a wide range of techniques from several theory-based domains at a low to medium dose. However, the type and dosage of the techniques used did vary across the two samples.

What is the Status of Multi-Informant Treatment Fidelity Research?

OBJECTIVE: The precise measurement of treatment fidelity (quantity and quality in the delivery of treatment strategies in an intervention) is essential for intervention development, evaluation, and implementation. Various informants are used in fidelity assessment (e.g., observers, practitioners [clinicians, teachers], clients), but these informants often do not agree on ratings. This scoping review aims to ascertain the state of science around multi-informant assessment of treatment fidelity. METHOD: A literature search of articles published through December 2021 identified 673 articles. Screening reduced the number of articles to 44, and the final study set included 35 articles. RESULTS: There was substantial variability across studies regarding study design, how fidelity was operationalized, and how reliability was defined and assessed. Most studies evaluated the agreement between independent observers and practitioner-report, though several other informant pairs were assessed. Overall, findings suggest that concordance across fidelity informants was low to moderate, with a few key exceptions. CONCLUSIONS: It is difficult to draw clear conclusions about the degree to which single versus multiple informant assessment is needed to produce an accurate and complete picture of treatment fidelity. The field needs to take steps to determine how to leverage multi-informant assessment to accurately assess treatment fidelity.

Core Elements of Family Therapy for Adolescent Behavioral Health Problems: Validity Generalization in Community Settings.

OBJECTIVE: The core elements of family therapy for adolescent mental health and substance use problems, originally distilled from high-fidelity sessions conducted by expert clinicians, were tested for validity generalization when delivered by community therapists in routine settings. METHOD: The study sampled recorded sessions from 161 cases participating in one of three treatment pools: implementation trial of Functional Family Therapy (98 sessions/50 cases/22 therapists), adaptation trial of Multisystemic Therapy (115 sessions/59 cases/2 therapists), and naturalistic trial of non-manualized family therapy in usual care (107 sessions/52 cases/21 therapists). Adolescents were identified as 60% male and 40% female with an average age of 15.4 years; 49% were Latinx, 27% White Non-Latinx, 15% African American, 3% another race/ethnicity, 6% race/ethnicity unknown. Session recordings (n = 320) were randomly selected for each case and coded for 21 discrete family therapy techniques. Archived data of one-year clinical outcomes were gathered. RESULTS: Confirmatory factor analyses replicated the factor structure from the original distillation study, retaining all four clinically coherent treatment modules comprised of all 21 techniques: Interactional Change (ICC = .77, Cronbach's α = .81); Relational Reframe (ICC = .75, α = .81); Adolescent Engagement (ICC = .72, α = .78); Relational Emphasis (ICC = .76, α = .80). Exploratory analyses found that greater use of core techniques predicted symptom improvements in one treatment pool. CONCLUSIONS: Core techniques of family therapy distilled from manualized treatments for adolescent behavioral health problems showed strong evidence of validity generalization, and initial evidence of links to client outcomes, in community settings.

Examining the Role of Student Responsiveness in Treatment Effects of a Tier 2 Program Targeting Reductions in Problem Behavior.

Student responsiveness's role in promoting intervention outcomes for students who exhibit problem behavior is understudied. Due to the relational nature of many interventions delivered by teachers that target social, emotional, or behavioral outcomes of students in classrooms, it is essential to assess how responsive students are to teachers' attempts to engage them in the intervention, particularly for students with problem behaviors that may impede teachers' attempts to engage these students in intervention effectively. In the current study, we combine samples from four randomized controlled trials to examine the relationship between student outcomes and teacher attempts to deliver BEST in CLASS, a Tier 2 intervention, via student responsiveness. Delivery of BEST in CLASS and student responsiveness were assessed through direct observations and teachers' reported measures. Results suggest that teacher adherence and competence in delivering BEST in CLASS practices was associated with reductions in problem behavior from pretest to post-test via student responsiveness. Limitations of the current study and implications for future research are discussed.

The Therapy Process Observational Coding System: Group cohesion scale in youth anxiety treatment: Psychometric properties.

BACKGROUND: There are no well-established measures of group cohesion, defined as the collaborative bond between group members, in group cognitive behavioral therapy (GCBT) with youth. We therefore examined the Therapy Process Observational Coding System for Child Psychotherapy-Group Cohesion Scale (TPOCS-GC), which has previously only been used with adult samples, in a youth sample. METHODS: Observers coded 32 sessions from 16 groups with 83 youth aged 8 to 15 years (90.7% European White). Youth had anxiety disorders and received manualized GCBT in community clinics. We examined psychometric properties of the TPOCS-GC and its' construct validity in terms of relations with pretreatment variables, alliance and fidelity during treatment, and post-treatment variables. Group cohesion was measured twice during treatment (early and late). RESULTS: The TPOCS-GC was internally consistent (α = 0.72) and was reliably coded (M ICC = 0.61). Higher clinical severity at pretreatment predicted lower early group cohesion. Higher youth age, higher clinical severity at pretreatment, and higher youth-rated early alliance predicted lower late group cohesion. Higher therapist-rated early alliance predicted higher early group cohesion. Higher therapist-rated late alliance predicted higher late group cohesion. Higher late group cohesion predicted lower clinical severity and higher client treatment satisfaction at post-treatment. Early group cohesion did not predict any post-treatment variables. CONCLUSIONS: A four-item version of the TPOCS-GC can be reliably used in youth GCBT. The TPOCS-GC is distinct from, but associated with, multiple clinical variables.

Study Protocol: Multi-level Determinants of Implementation and Sustainment in the Education Sector.

Evidence-based programs (EBPs) delivered in elementary schools show great promise in reducing risk for emotional and behavioral disorders (EBDs). However, efforts to sustain EBPs in school face barriers. Improving EBP sustainment thus represents a priority, but little research exists to inform the development of sustainment strategies. To address this gap, the Sustaining Evidenced-Based Innovations through Multi-level Implementation Constructs (SEISMIC) project will: (a) Determine if malleable individual, intervention, and organizational factors predict EBP treatment fidelity and modifications during implementation, sustainment, or both; (b) Assess the impact of EBP fidelity and modifications on child outcomes during implementation and sustainment; and (c) Explore the mechanisms through which individual, intervention, and organizational factors influence sustainment outcomes. This protocol paper describes SEISMIC, which builds upon a federally-funded RCT evaluating BEST in CLASS, a teacher-delivered program for K-3rd grade children at risk for EBDs. The sample will include 96 teachers, 384 children, and 12 elementary schools. A multi-level, interrupted time series design will be used to examine the relationship between baseline factors, treatment fidelity, modifications, and child outcomes, followed by a mixed-method approach to elucidate the mechanisms that influence sustainment outcomes. Findings will be used to create a strategy to improve EBP sustainment in schools.

To Utility and Beyond! Specifying and Advancing the Utility of Measurement-Based Care for Youth.

Mental health organizations that serve youth are under pressure to adopt measurement-based care (MBC), defined as the continuous collection of client-report data used to support clinical decision-making as part of standard care. However, few frameworks exist to help leadership ascertain how to select an MBC approach for a clinical setting. This paper seeks to define how an MBC approach can display clinical utility to provide such a framework. Broadly, we define clinical utility as evidence that an MBC approach assists stakeholders in fulfilling clinical goals related to care quality (i.e., improve client-clinician alliance and clinical outcomes) at the client (i.e., youth and caregiver), clinician, supervisor, and administrator levels. More specifically, our definition of clinical utility is divided into two categories relevant to the usability and usefulness of an MBC approach for a specific setting: (a) implementability (i.e., evidence indicating ease of use in a clinical setting) and (b) usefulness in aiding clinical activities (i.e., evidence indicating the potential to improve communication and make clinical activities related to care quality easier or more effective). These categories provide valuable information about how easy an MBC approach is to use and the potential benefits that the MBC data will confer. To detail how we arrived at this definition, we review prior definitions of clinical utility, discuss how previous definitions inform our definition of clinical utility for MBC, and provide examples of how the concept of clinical utility can be applied to MBC. We finish with a discussion of future research directions.

Treatment Fidelity and Outcome in CBT for Youth with Autism: The MEYA Fidelity Scale.

OBJECTIVE: Assessing treatment fidelity in effectiveness research is critical to interpreting study findings. This paper details the development and initial psychometric evaluation of the Modular Evidence-Based Practices for Youth with Autism Fidelity Scale (MEYA-FS) designed to support the assessment of cognitive-behavioral treatments for youth with autism in effectiveness research. METHOD: Recorded treatment sessions (N = 338) were randomly selected from 77 youth (M age = 9.65 years, SD = 1.87; 50.67% White; 85.33% male) who received the Schema, Emotion, and Behavior-Focused Therapy for Children (SEBASTIEN) (n = 51) or Coping Cat (n = 24) program. RESULTS: The MEYA-FS Adherence items displayed acceptable interrater reliability, but more than half of the MEYA-FS Competence items did not. The magnitude and pattern of correlations supported the score validity of the MEYA-FS Adherence and Competence items and subscales. However, some corresponding Adherence and Competence items displayed significant overlap. Scores on each Adherence subscale distinguished between the SEBASTIEN and Coping Cat programs, providing support for discriminant validity. Finally, higher Adherence and Competence subscales predicted significant improvements in youth clinical outcomes (adjustment problems in the school setting, social-communication difficulties, restrictive/repetitive behaviors, and externalizing problems), providing initial evidence for predictive validity. CONCLUSIONS: The psychometric properties of the MEYA-FS make it appropriate for supporting efforts to evaluate cognitive-behavioral interventions for youth with autism in effectiveness and implementation research.

Development and Initial Psychometrics of a Generic Treatment Integrity Measure Designed to Assess Practice Elements Targeting Social, Emotional, and Behavioral Outcomes in Early Childhood Settings.

Though treatment integrity measurement is important for research intended to promote social and behavioral outcomes of children at risk for emotional and behavioral disorders (EBDs) in early childhood settings, measurement gaps exist in the field. This paper reports on the development and preliminary psychometric assessment of the treatment integrity measure for early childhood settings (TIMECS), an observational measure designed to address existing measurement gaps related to treatment integrity with tier 2 interventions in the early childhood field. To assess the preliminary score reliability (interrater) and validity (construct, discriminant) of the TIMECS, live observations (N = 650) in early childhood classrooms from 54 teachers (92.6% female, 7.4% male; 61.1% White) and 91 children (M age = 4.53 years, SD = .44; 45.1% female, 54.9% male; 45.1% Black) at risk for EBDs were scored by 12 coders using the TIMECS and an observational measure designed to assess teacher-child interactions. Teachers also self-reported on the quality of the teacher-child relationship. Interrater reliability (intraclass correlation coefficients, ICC [2,2]) for the quantity (i.e., adherence) item scores had a mean of .81 (SD = .07; range from .68 to .95), and the quality (i.e., competence) item scores had a mean of .69 (SD = .08; range from .52 to .80). Scores on the TIMECS Quantity and Quality items and scales showed evidence of construct validity, with the magnitude of the correlations suggesting that the quantity and quality items assess distinct components of treatment integrity. A TIMECS quantity scale also showed promise for intervention evaluation research by discriminating between teachers who had and had not been trained in a specific evidence-based intervention targeting social and behavioral skills in early childhood. The findings support the potential of the TIMECS to assess treatment integrity of teacher-delivered practices designed to address child social and behavioral outcomes of children at risk for EBDs in early childhood settings.

The Pediatric Autism Spectrum Therapy Observation System: Development, Psychometric Properties, and Sensitivity to Treatment.

An observational coding system was developed to track clinical change in children with autism spectrum disorder (ASD) during psychotherapy. The Pediatric Autism Spectrum Therapy Observation System (PASTOS) consists of 23 items divided into 5 subscales and is used to rate child behaviors in individual psychotherapy sessions. Manual-based cognitive behavioral therapy session transcripts of 22 children diagnosed with ASD (IQ > 70) and a concurrent anxiety disorder (M = 9.41 years, SD = 1.56 years) enrolled in a randomized, controlled trial were coded. Results suggested that the PASTOS exhibited promising interrater reliability, internal consistency, convergent validity at post-treatment, and treatment sensitivity. The PASTOS may be a useful tool for studying process and outcome in psychotherapy research on children with ASD.

What Gets Measured Gets Done: How Mental Health Agencies can Leverage Measurement-Based Care for Better Patient Care, Clinician Supports, and Organizational Goals.

Mental health clinicians and administrators are increasingly asked to collect and report treatment outcome data despite numerous challenges to select and use instruments in routine practice. Measurement-based care (MBC) is an evidence-based practice for improving patient care. We propose that data collected from MBC processes with patients can be strategically leveraged by agencies to also support clinicians and respond to accountability requirements. MBC data elements are outlined using the Precision Mental Health Framework (Bickman et al. in Adm Policy Mental Health Mental Health Serv Res 43:271-276, 2016), practical guidance is provided for agency administrators, and conceptual examples illustrate strategic applications of one or more instruments to meet various needs throughout the organization.

Benchmarking Treatment Adherence and Therapist Competence in Individual Cognitive-Behavioral Treatment for Youth Anxiety Disorders.

Evidence-based treatments (EBTs) for youth are typically developed and established through studies in research settings designed to ensure treatment integrity, that is, protocol adherence and competence by therapists. An important question for implementation science is how well integrity is maintained when these EBTs are delivered in community settings. The present study investigated whether the integrity achieved by therapists in community settings achieved a benchmark set by therapists in a research setting when they delivered the same EBT-an individual cognitive-behavioral treatment (ICBT) for youth anxiety. Therapists (N = 29; 68.97% White; 13.79% male) provided ICBT to 68 youths (M age = 10.60 years, SD = 2.03; 82.35% White; 52.94% male) diagnosed with a principal anxiety disorder in research or community settings. Training and supervision protocols were the same across settings. Two independent teams of trained coders rated 744 sessions using observational instruments designed to assess ICBT adherence and competence. Both adherence and competence were higher in the research setting. Group differences in competence were consistent across treatment, but differences in adherence were most pronounced when treatment shifted to exposure, widely viewed as the most critical component of ICBT. When using the benchmarks from the research setting, therapists from the community settings fell short for indices of adherence and competence. However, given differences between therapists and clients, as well as the fact that treatment outcomes were similar across settings, our findings raise questions about whether it is appropriate to use treatment integrity benchmarks from research settings for community.

Core Elements of Family Therapy for Adolescent Behavior Problems: Empirical Distillation of Three Manualized Treatments.

Family therapy has the strongest evidence base for treating adolescent conduct and substance use problems, yet there remain substantial barriers to widespread delivery of this approach in community settings. This study aimed to promote the feasibility of implementing family-based interventions in usual care by empirically distilling the core practice elements of three manualized treatments. The study sampled 302 high-fidelity treatment sessions from 196 cases enrolled in 1 of 3 manualized family therapy models: multidimensional family therapy (102 sessions/56 cases), brief strategic family therapy (100 sessions/94 cases), or functional family therapy (100 sessions/46 cases). Adolescents were 57% male; 41% were African American, 31% White non-Hispanic, 9% Hispanic American, 6% another race/ethnicity, and 13% unknown. The observational fidelity measures of all three models were used to code all 302 sessions. Fidelity ratings were analyzed to derive model-shared treatment techniques via exploratory factor analyses on half the sample; the derived factors were then validated via confirmatory factor analyses supplemented by Bayesian structural equation modeling on the remaining half. Factor analyses distilled 4 clinically coherent practice elements with strong internal consistency: Interactional Change (6 treatment techniques; Cronbach's α = .93), Relational Reframe (7 techniques; α = .79), Adolescent Engagement (4 techniques; α = .68), and Relational Emphasis (4 techniques; α = .67). The 4 empirically derived factors represent the core elements of 3 manualized family therapy models for adolescent behavior problems, setting the foundation of a more sustainable option for delivering evidence-based family interventions in routine practice settings. Public Health Significance: Increasing implementation of high-fidelity family-based interventions would improve the quality of treatment services for adolescent conduct and substance use problems.

Development and Initial Psychometrics for a Therapist Competence Instrument for CBT for Youth Anxiety.

Therapist competence is an important component of treatment integrity. This article reports on the development and initial psychometric assessment of the Cognitive-Behavioral Treatment for Anxiety in Youth Competence Scale (CBAY-C), an observational instrument designed to capture therapist limited-domain competence (i.e., competence in the delivery of core interventions and delivery methods found in a specific psychosocial treatment program) in the delivery of the core practice elements in individual cognitive-behavioral treatment (ICBT) for youth anxiety. Treatment sessions (N = 744) from 68 youth participants (M age = 10.60 years, SD = 2.03; 82.3% Caucasian; 52.9% male) of the same ICBT program for youth anxiety from (a) an efficacy study and (b) an effectiveness study were independently scored by 4 coders using observational instruments designed to assess therapist competence, treatment adherence, treatment differentiation, alliance, and client involvement. Interrater reliability-intraclass correlation coefficients (2,2)-for the item scores averaged 0.69 (SD = 0.11). The CBAY-C item, scale, and subscale (Skills, Exposure) scores showed evidence of validity via associations with observational instruments of treatment adherence to ICBT for youth anxiety, theory-based domains (cognitive-behavioral treatment, psychodynamic, family, client centered), alliance, and client involvement. Important to note, although the CBAY-C scale, subscale, and item scores did overlap with a corresponding observational treatment adherence instrument independently rated by coders, the degree of overlap was moderate, indicating that the CBAY-C assesses a distinct component of treatment integrity. Applications of the instrument and future research directions discussed include the measurement of treatment integrity and testing integrity-outcome relations.

Factors Associated with Teacher Delivery of a Classroom-Based Tier 2 Prevention Program.

Teachers sometimes struggle to deliver evidence-based programs designed to prevent and ameliorate chronic problem behaviors of young children with integrity. Identifying factors associated with variations in the quantity and quality of delivery is thus an important goal for the field. This study investigated factors associated with teacher treatment integrity of BEST in CLASS, a tier-2 prevention program designed for young children at risk for developing emotional/behavioral disorders. Ninety-two early childhood teachers and 231 young children at-risk for emotional/behavioral disorders participated in the study. Latent growth curve analyses indicated that both adherence and competence of delivery increased across six observed time points. Results suggest that teacher education and initial levels of classroom quality may be important factors to consider when teachers deliver tier-2 (i.e., targeted to children who are not responsive to universal or tier-1 programming) prevention programs in early childhood settings. Teachers with higher levels of education delivered the program with more adherence and competence initially. Teachers with higher initial scores on the Emotional Support subscale of the Classroom Assessment Scoring System (CLASS) delivered the program with more competence initially and exhibited higher growth in both adherence and competence of delivery across time. Teachers with higher initial scores on the Classroom Organization subscale of the CLASS exhibited lower growth in adherence across time. Contrary to hypotheses, teacher self-efficacy did not predict adherence, and teachers who reported higher initial levels of Student Engagement self-efficacy exhibited lower growth in competence of delivery. Results are discussed in relation to teacher delivery of evidence-based programs in early childhood classrooms.

The global therapist competence scale for youth psychosocial treatment: Development and initial validation.

OBJECTIVE: We describe the development and initial psychometric properties of the observer-rated Global Therapist Competence Scale for Youth Psychosocial Treatment (G-COMP) in the context of cognitive-behavioral treatment (CBT) for youth anxiety disorders. METHOD: Independent coders rated 744 sessions from a sample of 68 youth (mean age = 10.56 years) using the G-COMP and the instruments of alliance, involvement, CBT adherence, CBT competence. RESULTS: Inter-rater reliability coefficients, ICC(2,2), were greater than .60 for the 5 G-COMP domain scores. G-COMP scores yielded small to medium correlations with instruments of alliance (rs = .17-.44) and youth involvement in treatment (rs = .08-.53), and medium to large correlations with instruments of CBT competence and adherence (rs = .26-.63). Therapists in the research setting were rated higher compared to newly trained therapists in community clinics. CONCLUSION: Preliminary reliability and validity of the G-COMP are promising, but future research is needed with non-CBT samples.

Identifying Common Practice Elements to Improve Social, Emotional, and Behavioral Outcomes of Young Children in Early Childhood Classrooms.

Educators are increasingly being encouraged to implement evidence-based interventions and practices to address the social, emotional, and behavioral needs of young children who exhibit problem behavior in early childhood settings. Given the nature of social-emotional learning during the early childhood years and the lack of a common set of core evidence-based practices within the early childhood literature, selection of instructional practices that foster positive social, emotional, and behavioral outcomes for children in early childhood settings can be difficult. The purpose of this paper is to report findings from a study designed to identify common practice elements found in comprehensive intervention models (i.e., manualized interventions that include a number of components) or discrete practices (i.e., a specific behavior or action) designed to target social, emotional, and behavioral learning of young children who exhibit problem behavior. We conducted a systematic review of early childhood classroom interventions that had been evaluated in randomized group designs, quasi-experimental designs, and single-case experimental designs. A total of 49 published articles were identified, and an iterative process was used to identify common practice elements. The practice elements were subsequently reviewed by experts in social-emotional and behavioral interventions for young children. Twenty-four practice elements were identified and classified into content (the goal or general principle that guides a practice element) and delivery (the way in which a teacher provides instruction to the child) categories. We discuss implications that the identification of these practice elements found in the early childhood literature has for efforts to implement models and practices.

Distilling the Core Elements of Family Therapy for Adolescent Substance Use: Conceptual and Empirical Solutions.

This article describes several barriers to widespread dissemination of manualized family-based treatments for adolescent substance use (ASU). We then offer a highly promising solution for adopting and sustaining family therapy in usual care: distilling the core practice elements of empirically validated family therapy models for ASU. We present a conceptual distillation of family therapy for ASU grounded in existing observational fidelity measures for three manualized models, a process that yielded four core elements: Family Engagement, Relational Reframing, Family Behavior Change, and Family Restructuring. We then introduce an innovative empirical method for distilling core elements that can serve as a template for rigorous distillation of other treatment approaches. Finally, we discuss how core elements can enhance family therapy services within the diverse workforce of usual care for ASU.

Therapist-youth agreement on alliance change predicts long-term outcome in CBT for anxiety disorders.

BACKGROUND: In individual cognitive behavioral therapy (ICBT) for youth anxiety disorders, it is unclear whether, and from whose perspective, the alliance predicts outcome. We examined whether youth- and therapist-rated alliance, including level of youth-therapist alliance agreement, predicted outcome in a randomized controlled trial. METHODS: Youth (N = 91, M age = 11.4 years (SD = 2.1), 49.5% boys, 86.8% Caucasian) diagnosed with separation anxiety disorder, social phobia, or generalized anxiety disorder drawn from the ICBT condition of an effectiveness trial were treated with an ICBT program. Youth- and therapist-rated alliance ratings, assessed with the Therapeutic Alliance Scale for Children (TASC-C/T), were collected following session 3 (early) and 7 (late). Early alliance, change in alliance from early to late, and level of youth-therapist agreement on early alliance and alliance change were examined, in relation to outcomes collected at posttreatment and 1-year follow-up. Outcome was defined as primary diagnosis loss and reduction in clinicians' severity ratings (CSR; Anxiety Disorders Interview Schedule; ADIS-C/P) based on youth- and parent-report at posttreatment and follow-up, and youth treatment satisfaction collected at posttreatment (Client Satisfaction Scale; CSS). RESULTS: Early TASC-C scores positively predicted treatment satisfaction at posttreatment. Higher levels of agreement on change in TASC-C and TASC-T scores early to late in treatment predicted diagnosis loss and CSR reduction at follow-up. CONCLUSIONS: Only the level of agreement in alliance change predicted follow-up outcomes in ICBT for youth anxiety disorders. The findings support further examination of the role that youth-therapist alliance discrepancies may play in promoting positive outcomes in ICBT for youth anxiety disorders. Clinical trial number NCT00586586, clinicaltrials.gov.