Overlap of obsessive compulsive and psychosis risk symptoms in a specialized clinic.

AIM: Psychotic disorders and obsessive-compulsive disorder (OCD) commonly co-occur. Likewise, subthreshold psychosis symptoms (clinical high risk for psychosis; CHR) and obsessive compulsive symptoms (OCS) often overlap and may be difficult to differentiate. This study aimed to replicate research investigating the prevalence of OCD in a CHR clinic sample, validate and investigate factor structure of a self-report OCS measure in a CHR sample, explore how OCS may relate to CHR and co-occurring symptoms, and investigate whether real-world CHR treatment improves OCS and CHR symptoms. METHOD: This study analysed archival clinical data from baseline and 6-month follow-up assessments collected by a specialist outpatient CHR clinic. Data included assessments of CHR symptoms, OCS, and clinician-rated diagnosis. Exploratory factor analysis examined the OCS measure. RESULTS: Within this CHR clinic sample, 13.5% experienced co-morbid OCD. The self-report OCS measure had two factors: (1) checking and counting behaviours and (2) intrusive thoughts and images of harm/guilt. The checking and counting factor correlated with depression and social anxiety. The intrusive thoughts and images of harm/guilt factor significantly correlated with unusual thought content and social anxiety. Between baseline to 6-month follow-up, clients exhibited CHR symptom improvement regardless of OCD diagnosis. However, OCS did not change. CONCLUSIONS: These findings support validity of a self-report OCS measure in a CHR clinic sample and that types of OCS experiences may exhibit different clinical patterns. Additionally, it appears that individuals with comorbid OCD responded similarly to CHR treatment compared to those without OCD.

Race/ethnicity and socioeconomic status as predictors of outcome following family therapy in youth at clinical high risk for psychosis.

AIM: There is limited research on the effects of sociodemographic and socioeconomic factors on treatment outcomes in youth at clinical high risk for psychosis (CHRp). This study examined sociodemographic factors that may affect functional outcomes within this population. Specifically, we investigated the influence of race/ethnicity (dichotomized as non-Hispanic whites [NHW] vs. people of colour [POC]), socioeconomic status (SES; operationalized as parental years of education), and their interaction on change in psychosocial functioning and symptoms over 6 months in a randomized trial of family-focused therapy. METHODS: CHRp youth (N = 128) participated in a randomized trial of family therapy (18 sessions of family therapy vs. 3 sessions of family psychoeducation). Sixty-four participants who self-identified as POC and 64 self-identified NHW participants completed baseline and 6-month follow-up measures of positive and negative symptoms and psychosocial (global, role, and social) functioning. Multiple regression models were conducted to test the main effect of race/ethnicity on changes in positive and negative symptoms and functioning, and whether this effect was moderated by parental education. RESULTS: There was a significant interaction between race/ethnicity and parental education, such that higher parental education was associated with greater improvement in global functioning in NHW participants, but there was no relationship between parental education and global functioning in POC. Additionally, higher parental education was associated with a decrease in negative symptoms in NHW participants but not in POC. There were no significant effects of race/ethnicity or parental education on positive symptoms, nor on social or role functioning. CONCLUSIONS: Clinicians may consider tailoring psychosocial treatments according to the needs of diverse families who vary in sociodemographic factors such as educational attainment and race/ethnicity.

Gender-affirming care in the assessment and treatment of psychosis risk: Considering minority stress in current practice and future research.

INTRODUCTION: Although research has documented the marked disparities in rates of psychosis-spectrum diagnoses in various socially marginalized populations, there is limited research addressing the needs of gender expansive individuals in the context of psychosis-spectrum illnesses using a minority stress lens. As clinical high-risk for psychosis (CHR-p) assessment and treatment becomes accessible to increasingly diverse populations, there is a need for clinicians to demonstrate greater clinical competency working with individuals across diverse social backgrounds and identities. METHODS: We examined rates of gender expansive (GE) patients seeking evaluation at an urban-based CHR-p clinic and compared the diagnostic profile of GE individuals to cisgender patients. Post-hoc analyses were conducted on clinical variables with significant differences between the cisgender and GE groups. RESULTS: The proportion of GE patients seeking evaluation increased from 2017 (9.3%) to 2021 (16.7%). Compared to cisgender youth, GE patients had significantly higher depressive, social anxiety, borderline personality disorder symptoms, higher levels of suicidality and non-suicidal self-injurious behaviour, and lower role functioning. Gender identity was predictive of suicidality controlling for social anxiety, borderline symptoms, and role functioning. CONCLUSIONS: We review implications for CHR-p treatment and discuss ways to integrate minority stress theory and gender-affirming practices into coordinated specialty care for CHR-p patients.

Reduced Expression of Emotion: A Red Flag Signalling Conversion to Psychosis in Clinical High Risk for Psychosis (CHR-P) Populations.

Objective: In this hypothesis-testing study, which is based on findings from a previous atheoretical machine-learning study, we test the predictive power of baseline "reduced expression of emotion" for psychosis.Method: Study participants (N = 96, mean age 16.55 years) were recruited from the Prevention of Psychosis Study in Rogaland, Norway. The Structured Interview for Prodromal Syndromes (SIPS) was conducted 13 times over two years. Reduced expression of emotion was added to positive symptoms at baseline (P1-P5) as a predictor of psychosis onset over a two-year period using logistic regression.Results: Participants with a score above zero on expression of emotion had over eight times the odds of conversion (OR = 8.69, p < .001). Data indicated a significant dose-response association. A model including reduced expression of emotion at baseline together with the positive symptoms of the SIPS rendered the latter statistically insignificant.Conclusions: The study findings confirm findings from the previous machine-learning study, indicating that observing reduced expression of emotion may serve two purposes: first, it may add predictive value to psychosis conversion, and second, it is readily observable. This may facilitate detection of those most at risk within the clinical high risk of psychosis population, as well as those at clinical high risk. A next step could be including this symptom within current high-risk criteria. Future research should consolidate these findings.

Neurocognitive and social cognitive training for youth at clinical high risk (CHR) for psychosis: A randomized controlled feasibility trial.

BACKGROUND: Cognitive deficits are present in individuals at clinical high risk for psychosis (CHRP). We developed Cognition for Learning and for Understanding Everyday Social Situations (CLUES), an integrated social- and neurocognitive remediation intervention for CHRP, and examined its feasibility and efficacy compared to an active control intervention in a pilot randomized controlled trial. METHOD: Thirty-eight individuals at CHR-P were randomized to CLUES or Enriched Acceptance and Commitment Therapy (EnACT). Participants were assessed at baseline, end of treatment and 3-month follow-up for changes in social/role functioning, neuro- and social cognition, and symptoms. RESULTS: Social functioning significantly improved for participants in CLUES over EnACT, at end of treatment and 3-month follow-up. CLUES participants also showed greater improvements in social cognition (theory of mind and managing emotions). CONCLUSION: The results support feasibility of CLUES and suggest preliminary efficacy. Future randomized controlled trials of CLUES in a larger sample, with additional treatment sites, could help determine efficacy of CLUES, and investigate whether CLUES can be effectively implemented in other settings.

Family-focused therapy for individuals at high clinical risk for psychosis: A confirmatory efficacy trial.

AIMS: Young people with attenuated psychotic symptoms (APS), brief intermittent psychosis, and/or genetic risk and functional deterioration are at high risk for developing psychotic disorders. In a prior trial, family-focused therapy for clinical high risk youth (FFT-CHR) was more effective than brief psychoeducation in reducing APS severity over 6 months. This 7-site trial will compare the efficacy of FFT-CHR to a psychoeducational and supportive intervention (enhanced care) on APS and social functioning in CHR individuals over 18 months. METHODS: Participants (N = 220, ages 13-25 years) with a CHR syndrome will be randomly assigned to FFT-CHR (18 1-h sessions of family psychoeducation and communication/problem-solving skills training) or enhanced care (3 1-h family psychoeducational sessions followed by 5 individual support sessions), both given over 6 months. Participants will rate their weekly progress during treatment using a mobile-enhanced online platform. Family communication will be assessed in a laboratory interactional task at baseline and post-treatment. Independent evaluators will assess APS (primary outcome) and psychosocial functioning (secondary outcome) every 6 months over 18 months. RESULTS: We hypothesize that, compared to enhanced care, FFT-CHR will be associated with greater improvements in APS and psychosocial functioning over 18 months. Secondarily, improvements in family communication over 6 months will mediate the relationship between treatment condition and primary and secondary outcomes over 18 months. The effects of FFT-CHR are predicted to be greater in individuals with higher baseline risk for psychosis conversion. CONCLUSIONS: Results of the trial will inform treatment guidelines for individuals at high risk for psychosis.

Exploring specific predictors of psychosis onset over a 2-year period: A decision-tree model.

AIM: The fluctuating symptoms of clinical high risk for psychosis hamper conversion prediction models. Exploring specific symptoms using machine-learning has proven fruitful in accommodating this challenge. The aim of this study is to explore specific predictors and generate atheoretical hypotheses of onset using a close-monitoring, machine-learning approach. METHODS: Study participants, N = 96, mean age 16.55 years, male to female ratio 46:54%, were recruited from the Prevention of Psychosis Study in Rogaland, Norway. Participants were assessed using the Structured Interview for Psychosis Risk Syndromes (SIPS) at 13 separate assessment time points across 2 years, yielding 247 specific scores. A machine-learning decision-tree analysis (i) examined potential SIPS predictors of psychosis conversion and (ii) hierarchically ranked predictors of psychosis conversion. RESULTS: Four out of 247 specific SIPS symptom scores were significant: (i) reduced expression of emotion at baseline, (ii) experience of emotions and self at 5 months, (iii) perceptual abnormalities/hallucinations at 3 months and (iv) ideational richness at 6 months. No SIPS symptom scores obtained after 6 months of follow-up predicted psychosis. CONCLUSIONS: Study findings suggest that early negative symptoms, particularly those observable by peers and arguably a risk factor for social exclusion, were predictive of psychosis. Self-expression and social behaviour might prove relevant entry points for early intervention in psychosis and psychosis risk. Testing study results in larger samples and at other sites is warranted.

Individualized vocational and educational support and training for youth at clinical high risk for psychosis.

AIM: Early intervention for psychosis has been of high interest in the past two decades. Research demonstrates that clinical high risk for psychosis (CHR-p) populations experience impairments in role functioning. Although several vocational and cognitive interventions exist for people living with psychosis, there are no known evidence-based treatments for role functioning difficulties during the CHR-p stage. There is clear evidence for a need for interventions that directly target role functioning. METHODS: This paper describes the theoretical development and implementation of a novel intervention targeting role functioning impairments: Individualized Vocational and Educational Support and Training (InVEST). The CEDAR Clinic, a specialized CHR-p coordinated specialty care (CSC) team, has worked to develop InVEST to target core aspects of role functioning, namely executive functioning, stress sensitivity, and task initiation. The intervention is cost-efficient, as bachelor level clinicians provide the service under supervision of licensed clinicians. This summary describes InVEST, provides a disguised case example, and presents initial exploratory data (N = 135) focused on the intervention's feasibility in this CSC program. RESULTS: Although these preliminary data are limited, available information suggests that InVEST may provide a core treatment modality within CHR-p treatment programs. CONCLUSIONS: More research formally investigating InVEST with a larger sample would provide further evidence of the intervention's efficacy.

Treatment outcomes for young people at clinical high risk for psychosis: Data from a specialized clinic.

AIM: Treatment for youth exhibiting signs of clinical high risk for psychosis (CHR-P) has been emphasized in recent years, but there is need for a greater understanding of the course of symptoms and functioning across treatment. The aim of this study is to describe 10 years of naturalistic treatment outcomes in a real-world, specialized CHR-P outpatient clinic, the Center for Early Detection, Assessment, and Response to Risk (CEDAR) Clinic. METHODS: The CEDAR Clinic routinely collects client outcomes data for the purposes of program development, monitoring treatment effectiveness, and characterizing the clinic population. Clients are assessed at baseline, every 6 months (for up to 2 years depending on duration of treatment), and at the end of treatment. A series of mixed-effects models were performed to analyse change over time in outcomes (symptoms and functioning) between baseline and follow-up time points. RESULTS: Over time, clients' (N = 123) positive (F = 11.8, p < .001) and negative (F = 4.91, p = .002) symptoms declined relative to their baseline. Social functioning improved over time (F = 2.50, p = .049), as did depression (F = 8.60, p < .001) and hopelessness (F = 4.21, p = .004). Clients' total CEDAR treatment hours ranged across type of treatment service, but the amount of treatment clients received was not associated with any clinical outcomes. CONCLUSIONS: Over the course of treatment at this real-world, specialized CHR-P program, clients exhibited significant improvement in clinical outcomes and did not significantly decline in any measured outcomes. We discuss this study in the context of current understanding and guidelines for specialized coordinated specialty care treatment for CHR-P.

"Real-world" first-episode psychosis care in Massachusetts: Lessons learned from a pilot implementation of harmonized data collection.

AIM: Increasing evidence points to the value of coordinated specialty care (CSC) for early intervention in psychotic disorders. This report characterizes clinical and socio-demographic features of patients at CSC programs in Massachusetts (MA), assessed by a standardized battery incorporated into "real-world" clinical care. METHODS: The MA psychosis network for early treatment developed a pilot battery to coordinate assessments across six CSC clinics. Programs reported baseline, 6-month, and 12-month data from a sample of 287 patients with intake dates ranging from April 2015 to December 2020. RESULTS: Patients showed improvements in functioning, emergency service use and several symptom domains at 6 and 12 months. Missing data proved to be a limitation. CONCLUSIONS: Patients improved on several meaningful domains within the first year of CSC treatment. Future implementation efforts in cross-program data collection should consider strategies to circumvent limitations related to heterogeneity between clinics, patient discharge and clinics' capacity for data collection.

Changes in community providers' screening behaviours, referral practices, and clinical confidence following participation in an early psychosis educational campaign.

AIM: Successful delivery of care to individuals with early psychosis depends on the ability of community providers to identify and refer appropriate candidates for services. Although specialty centres commonly rely upon education and outreach campaigns to building bridges with community providers, few studies have examined the effectiveness of these campaigns or the mechanisms by which they may achieve their intended effects. METHODS: We surveyed community clinicians (N = 39) about their screening behaviours, referral practices, and confidence in managing early psychosis just before and 3-6 months after attending an educational event designed to promote recognition and quality treatment of early psychosis. RESULTS: Three to six months following attendance, providers reported screening a greater proportion of clients for early psychosis, referring a greater number of clients to specialty services, and feeling more confident in their ability to respond to clients with early psychosis. Increases in confidence following attendance were associated with corresponding increases in screening behaviour. CONCLUSIONS: The results suggest that outreach campaigns designed to enhance community providers' knowledge about early psychosis assessment and resources may be effective in promoting screening, referrals, and confidence in managing psychosis. Gains in provider confidence may contribute to increases in screening. Given the lack of control group and relatively short follow-up period, more research is needed to determine the effects of early psychosis educational events and the mechanisms by which they may promote successful treatment delivery for young people in need.

Implementation case study: Multifamily group intervention in first-episode psychosis programs.

AIM: Family interventions are a core component of first-episode psychosis (FEP) treatment; however, low implementation rates are consistently reported. As such, work is needed to understand the factors impacting real-world treatment delivery. The present paper describes the implementation of the McFarlane-model multifamily psychoeducational groups (MFG) in established FEP early intervention programs within a single state. The aims were to examine (a) training participation and implementation of MFG, (b) barriers and facilitators to implementation, and (c) modifications made to MFG. METHODS: Practitioners from six established FEP early intervention programs received in-person training and ongoing consultation in MFG. Training participation data were obtained via attendance and implementation outcomes were obtained from practitioner reports. Fifteen months following the initial training, practitioners reported on clinic-specific barriers, facilitators, and modifications across four categories (context, intervention, practitioner, and recipient). RESULTS: Twenty-three practitioners across six clinics received in-person training and were offered ongoing consultation to support implementation. Difficulties in starting MFG were salient as the earliest group was run 7 months after the initial training, thereby resulting in low overall frequency of groups. A number of barriers spanning context, intervention, practitioner, and recipient domains were noted, the majority of which were clinic-specific. Despite challenges, practitioners identified several facilitators and made modifications to the intervention and its delivery in service of implementation. CONCLUSIONS: Results from this implementation case study highlighted the challenges of delivering MFG in real-world FEP early intervention programs. Further, this paper emphasizes the value in identifying and addressing clinic-specific factors when implementing MFG.

A comparison of neurocognition and functioning in first episode psychosis populations: do research samples reflect the real world?

PURPOSE: The current study evaluates the demographic, clinical, and neurocognitive characteristics of a recruited FEP research sample, a research control group, and a FEP clinic sample that were assessed and treated within the same center and time period. METHODS: This study utilized data collected through an observational study and a retrospective chart review. Samples were ascertained in the Longitudinal Assessment and Monitoring of Clinical Status and Brain Function in Adolescents and Adults study and the Prevention and Recovery in Early Psychosis clinic. FEP clinic patients (n = 77), FEP research participants (n = 44), and age-matched controls (n = 38) were assessed using the MATRICS consensus cognitive battery and global functioning social and role scales. Between-group differences were assessed via one-way ANOVA and Chi-square analyses. RESULTS: No significant differences were observed between groups with regard to age and gender. The FEP research sample had a higher proportion of white participants, better social and role functioning, and better neurocognitive performance when compared with the FEP clinical population. The clinic sample also had more diagnostic variability and higher prevalence of substance use disorders relative to the FEP research sample. CONCLUSIONS: Researchers should be aware of how study design and recruitment practices may impact the representativeness of samples, with particular concern for equal representation of racial minorities and patients with more severe illness. Studies should be designed to minimize burden to promote a wider range of participation.

Clinical high risk for psychosis: The effects of labelling on public stigma in a undergraduate population.

AIM: Schizophrenia is a highly stigmatized disorder. Identification of youth at high risk for psychosis has the potential for improved outcomes. However, identifying youth at risk could subject them to increased public stigma. Using an experimental vignette design, this study examined relative levels of public stigma elicited by the labels "schizophrenia," "clinical high risk (CHR)," "attenuated psychotic symptoms syndrome (APSS)," a label implying normative adolescent development ("a bad breakup"), and a no-label control condition. METHODS: Ninety-six undergraduates (age: 18.8 + 1.1, range: 18-22) read a vignette describing an adolescent experiencing symptoms typical of CHR for psychosis. The vignette label (APSS, CHR, schizophrenia, a bad breakup or no label) was counterbalanced between participants. Participants answered questions assessing stigma toward the individual and their prior knowledge of and familiarity with psychosis. RESULTS: Overall stigma did not differ across conditions. Only ratings of personal responsibility were higher for the breakup label than the schizophrenia label (P < .05). More prior knowledge about, and higher familiarity with, psychotic symptoms predicted lower overall stigma. CONCLUSION: We did not find that schizophrenia, CHR or APSS labels elicited elevated stigma in this sample relative to the control labels. This may reflect relatively low levels of mental health stigma in the group studied, a new finding inconsistent with earlier work. Greater levels of knowledge about and familiarity with psychosis were associated with lower stigma. These findings reinforce the potential for mental health awareness campaigns to reduce stigma but also raise questions about factors contributing to lower rates of stigma.

Development of a Boston Treatment Program for Youth at Clinical High Risk for Psychosis: Center for Early Detection, Assessment, and Response to Risk (CEDAR).

Over the past two decades, increasing attention has been given to the importance of early intervention for psychosis. This article describes the development of the Center for Early Detection, Assessment and Response to Risk (CEDAR), which focuses on early identification and treatment of youth at clinical high risk for psychosis. There are relatively few models in the United States for such programs, and we present our developmental story, focusing mainly on the CEDAR Clinic, as a case study of how such a program can develop. We describe the rationale, infrastructure, and services provided at the CEDAR Clinic, and present some descriptive data from the CEDAR Clinic through 2016. A case example is provided to illustrate treatment at CEDAR. We hope that the cultural history of our program's development is informative for clinicians and policy makers as one model of how to build an early intervention service. We believe that this article is timely in view of the growing momentum in the United States for developing programs for intervening as early as possible for youth at clinical high risk for psychosis.

Longitudinal determinants of client treatment satisfaction in an intensive first-episode psychosis treatment programme.

AIM: Previous evidence demonstrates that higher treatment satisfaction is strongly associated with improved clinical outcomes and functioning. The aim of the current study is to explore potential associations between clinical and demographic attributes, as well as changes in role, social and cognitive functioning occurring over the course of treatment, on self-reported treatment satisfaction within the context of an intensive first-episode psychosis intervention programme. METHODS: Forty-four young adults attending a first-episode psychosis treatment programme completed a battery of clinical and neuropsychological measures at intake to the programme and again after 6 months of treatment. A modified version of the Client Satisfaction Questionnaire was administered at 6 months. Baseline, 6-month and change scores across the clinical and demographic measures were examined relative to the satisfaction questionnaire to evaluate determinants of treatment satisfaction. RESULTS: Better premorbid adjustment during childhood and early adolescence was associated with higher treatment satisfaction, as did positive changes in clients' cognitive performance and their use of humour as a coping strategy. Clients' use of emotional support as a coping strategy at 6 months was also positively associated with treatment satisfaction. Although clients' social and role functioning improved significantly during the 6-month treatment window, changes in functional outcomes were not significantly associated with treatment satisfaction. CONCLUSIONS: The current study highlights the role of premorbid adjustment and changes in coping and neurocognition as factors influencing treatment satisfaction. Future research designs might be able to more specifically ascertain causal relationships between patient characteristics, treatment components, client satisfaction and clinical effects.

The impact of premorbid adjustment, neurocognition, and depression on social and role functioning in patients in an early psychosis treatment program.

OBJECTIVE: Functional impairments are debilitating concomitants of psychotic disorders and are present early in the illness course and, commonly, prior to psychosis onset. The factors affecting social and role functioning in early psychosis (EP) following treatment are unclear. We evaluated whether six months of participation in the PREP(R), Boston, EP treatment program, part of a public-academic community mental health center, was related to improvements in social and role functioning and whether premorbid adjustment in adolescence, baseline neurocognition, and depression symptoms predicted functional improvement. METHOD: The Global Functioning Social and Role scales, MATRICS neurocognitive battery, and Calgary Depression Scale were assessed at baseline and six months during naturalistic treatment, while premorbid adjustment was measured at baseline. All participants were psychotic disorder patients in PREP(R) (n = 46 with social functioning and 47 with role functioning measures at both time points). RESULTS: Large improvements were observed in role functioning (d = 0.84) and medium to large improvements were observed in social functioning (d = 0.70). Models consisting of adolescent premorbid adjustment and change in depression symptoms predicted social and role functioning change, whereas neuropsychological functioning did not. CONCLUSIONS: Substantial improvements in social and role functioning were observed among this sample participating in a recovery-based EP program. The impact of clinical factors on social and role functioning was highlighted. Further studies of premorbid adjustment in adolescence and the treatment of depression in EP programs in controlled treatment trials are needed to confirm these findings.

Reducing the duration of untreated psychosis and its impact in the U.S.: the STEP-ED study.

BACKGROUND: Early intervention services for psychotic disorders optimally interlock strategies to deliver: (i) Early Detection (ED) to shorten the time between onset of psychotic symptoms and effective treatment (i.e. Duration of Untreated Psychosis, DUP); and (ii) comprehensive intervention during the subsequent 2 to 5 years. In the latter category, are teams ('First-episode Services' or FES) that integrate several empirically supported treatments and adapt their delivery to younger patients and caregivers. There is an urgent need to hasten access to established FES in the U.S. Despite improved outcomes for those in treatment, these FES routinely engage patients a year or more after psychosis onset. The Scandinavian TIPS study was able to effectively reduce DUP in a defined geographic catchment. The guiding questions for this study are: can a U.S. adaptation of the TIPS approach to ED substantially reduce DUP and improve outcomes beyond existing FES? METHODS/DESIGN: The primary aim is to determine whether ED can reduce DUP in the US, as compared to usual detection. ED will be implemented by one FES (STEP) based in southern Connecticut, and usual detection efforts will continue at a comparable FES (PREP(R)) serving the greater Boston metropolitan area. The secondary aim is to determine whether DUP reduction can improve presentation, engagement and early outcomes in FES care. A quasi-experimental design will compare the impact of ED on DUP at STEP compared to PREP(R) over 3 successive campaign years. The campaign will deploy 3 components that seek to transform pathways to care in 8 towns surrounding STEP. Social marketing approaches will inform a public education campaign to enable rapid and effective help-seeking behavior. Professional outreach and detailing to a wide variety of care providers, including those in the healthcare, educational and judicial sectors, will facilitate rapid redirection of appropriate patients to STEP. Finally, performance improvement measures within STEP will hasten engagement upon referral. DISCUSSION: STEP-ED will test an ED campaign adapted to heterogeneous U.S. pathways to care while also improving our understanding of these pathways and their impact on early outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02069925 . Registered 20 February 2014.